System and methods for triggering a radiofrequency transceiver in the human body

ABSTRACT

Systems and methods described herein use near field communications to locate a radiating transponder, such as a pill swallowed by a patient. The system can be triggered to turn on and transmit a waveform to a set of antennas attached to, coupled with, or near the patient. The magnetic field emitted by the transponder can be measured by the receiving antennas, for example, using principles of mutual inductance. The differential phase and/or time shifts between the antennas can contain sufficient information to find the location of the transponder and optionally its orientation relative to body coordinates. The system can display the location and/or orientation of the transponder. Further, the pill can include a reservoir to deliver a payload at a particular site of the patient&#39;s body based at least in part on the determined location.

RELATED APPLICATIONS

This application claims priority under 35 U.S.C § 119(e) as anonprovisional of U.S. Provisional Application 61/969,946, filed Mar.25, 2014, titled “System for Location-Based Drug Dosage and Delivery inthe Gastrointestinal System”, and is a continuation-in-part of U.S.application Ser. No. 13/969,423, filed Aug. 16, 2013, titled “System andMethods for Locating Relative Positions of Multiple Patient Antennas,”which claims priority to U.S. Provisional Application No. 61/784,340,filed Mar. 14, 2013, titled SYSTEM FOR LOCATING RADIOFREQUENCYTRANSCEIVER IN THE HUMAN BODY, and U.S. Provisional Application No.61/683,851, filed Aug. 16, 2012, titled MOTILITY PILL GASTROINTESTINALMONITORING SYSTEM. The disclosures of each of the foregoing applicationsare hereby incorporated by reference in their entirety.

BACKGROUND

Movement of food through the human digestive tract can be obstructed orslowed for a variety of reasons. Frequently, there may be little or nopain, yet the condition may result in death if the condition is notidentified and treated quickly. Reasons for gastrointestinal (GI)dismotility are numerous, including bowel strangulation, neuropathy,diverticulitus, paraplegia, diabetic gastroparesis, chemotherapy, mentalconditions, and drug interaction. People of some or all ages can beaffected, ranging from newborn babies to the elderly.

BRIEF DESCRIPTION OF THE DRAWINGS

Throughout the drawings, reference numbers are re-used to indicatecorrespondence between referenced elements. The drawings are provided toillustrate embodiments of the features described herein and not to limitthe scope thereof.

FIGS. 1A-B are block diagrams illustrating transponder monitoringsystems in accordance with embodiments of the disclosure.

FIG. 2A is a block diagram illustrating a transmitter pill in accordancewith an embodiment of the disclosure.

FIG. 2B illustrates a cross section view of a pill transmitter inaccordance with an embodiment of the disclosure.

FIG. 2C illustrates a model circuit diagram for the pill transmitter inaccordance with an embodiment of the disclosure.

FIG. 3 illustrates a plurality of transceiver units in connection with apatient monitor in accordance with an embodiment of the disclosure.

FIG. 4 illustrates an embodiment of a process for calculating thelocation of a pill transmitter.

FIG. 5 illustrates an embodiment of a process for dynamicallycalculating positions of a plurality of antennas.

FIGS. 6A and B illustrate an embodiment of a process for usingmulti-multilateration analysis to dynamically calculate the positions ofa plurality of antennas.

FIGS. 7A and B illustrate an embodiment of a process for the dynamicallycalculating the locations of plurality of antennas in addition tocalculating the location of a pill.

FIG. 8A illustrates an embodiment of a process for calculating initialcalibration parameters.

FIG. 8B illustrates a system for measuring calibration parameters inaccordance to an embodiment of the disclosure.

FIG. 9 illustrates a block diagram for a location estimator moduleaccording to an embodiment of the disclosure.

FIG. 10 illustrates a patient monitor including a display according toan embodiment of the disclosure.

FIG. 11A illustrates a system for using antenna coordinates according toan embodiment of the disclosure.

FIGS. 11B and C illustrate model diagrams for antenna interactions inaccordance with an embodiment of the disclosure.

FIG. 12 is a block diagram illustrating an embodiment of a transponderactivating system 1200 in accordance with embodiments of the disclosure.

FIG. 13 is a block diagram illustrating an embodiment of a transmitterpill in accordance with an embodiment of the disclosure.

FIG. 14 illustrates an embodiment of a process for sending a triggersignal to a pill transmitter

DETAILED DESCRIPTION

Various embodiments will be described hereinafter with reference to theaccompanying drawings. These embodiments are illustrated and describedby example only, and are not intended to be limiting.

I. Problems with Current GI Tract Monitoring Techniques

For the past decade, the gastrointestinal (“GI”) tract has become anarea of intense scientific and public interest due to excitingdiscoveries of its importance in many aspects of human health anddisease. However, understanding the pathophysiology of manygastrointestinal disorders is hampered by an inadequate ability toinvestigate primary GI functions with a technological means providinglow patient stress, rapid and effective diagnostic data, and ease of useenabling universal adoption.

Science's limited knowledge of various GI problems is especially evidentin the expanding obese population who are at high risk of developingdiabetes mellitus. Diabetic patients frequently suffer fromgastrointestinal dysmotility such as gastroparesis, a functional delayin the emptying of the stomach in the absence of mechanical obstruction.Symptoms usually include early satiety, nausea, vomiting, bloating, andmay be associated with erratic blood sugar control due to variablestomach emptying. These symptoms afflict as many as 12% of the diabeticpopulation and are only assumed to be resultant from gastroparesis. Atthis time, the diagnostic tools to prove certainty are unavailable.

Outside the diabetic group, many other patient populations couldimmediately benefit from a safer, more readily available, and moreprecise technology to evaluate GI function as it relates to feedingintolerance. These populations are wide ranging and include infants,post-surgical patients, mechanical obstruction patients, and those inIntensive Care Units. This group alone engenders a substantial financialimpact due to both increased length of hospital stay and morbidity andmortality due to nutritional inadequacies. Feeding intolerance andpresumed GI dysmotility, including chronic constipation, is frequentlyreported in children with (and infants at risk for) Autism SpectrumDisorder. Patients can spinal cord injuries (SCI) would greatly benefitin quality of life with a real-time motility monitoring system. Patientswith endocrine disorders such as hypo/hyperthyroidism, pituitary andparathyroid disease, and Addison's disease; as well as large percentagesof the population with functional dyspepsia, refractory irritable bowelsyndrome, post-infectious and idiopathic gastroparesis, narcotic bowelsyndrome and Oglevie's syndrome would also benefit from improved GItract diagnosis technology.

The inadequacy of our current technical ability to evaluate GI tractpathophysiology is hindering diagnosis and treatment. If we can diagnoseand understand the problems more intricately and with greater fidelity,we can be able to develop new nutritional, pharmacologic,electromechanical, and surgical solutions to treat them. In doing so, wecan significantly improve the quality of life of those afflicted.

Initial diagnosis of problematic gastric emptying can be tested to ruleout obstruction. Typically this is performed either invasively via upperendoscopy or externally using barium X-ray techniques entailingradiation exposure. Today, nuclear scintigraphy is the gold standard forestimating gastric emptying. This utilizes ingestion of a radioisotope(Tc-99m sulfur colloid) labeled egg salad sandwich followed byscintiscanning every 15 minutes for 4 hours. This subjects the patientto radiation exposure equal to ⅓ of what is experienced annually fromnatural sources (USA) and involves very expensive specialized equipmentand expertise.

Alternate diagnostic procedures for assessing gastric emptying useradio-opaque markers tracked through serial X-ray imaging. Althoughsimple and relatively inexpensive, this method measures the emptying oflarge non-digestible markers instead of physiologically relevant solidswhich only provides a partial indicator of the situation. A breath testis also available to estimate gastric emptying after aradioisotope-labeled meal is ingested. The stable isotope, usually¹³CO₂, is incorporated into the carbon dioxide exhaled which can berecovered and sent to a reference laboratory for determination.

There are existing radiofrequency (RF) location techniques that use thereturned power from a wireless transmitting tag to estimate location byradio direction finding. The technique is not accurate, doing only avery rough 2-dimensional (2D) tag location. Lastly, there is limitedexperience in bowel motility evaluation with a device called theSmartPill™ by Given Imaging™. This device utilizes pH, temperature andpressure data to determine a very rough position in the bowel. Thisdevice is too large to be treated in the same manner as food particlesby the stomach, thus limiting its usefulness, especially in pediatricpopulations. Another pill device available from Given Imaging™, calledthe PillCam™, performs a capsule endoscopy to obtain GI tract video. ThePillCam™ is also a relatively large pill and does not provide anylocation-finding mechanism.

II. Proposed Solution Overview

Prior methods for monitoring GI tract health typically fail to provide ameans to continuously monitor GI peristalsis and/or motility health anddo not support this monitoring in a home or care facility environment.It would be beneficial to provide a highly effective, simple toimplement, and inexpensive monitoring system to measure GI motility andgeneral GI tract function. Certain embodiments of the systems describedherein can provide some or all such benefits, overcome shortfalls ofexisting monitoring solutions, can be applicable to a variety ofhealthcare applications, and can be flexible and extendable to thetreatment, research, and monitoring of many other GI diseases andconditions.

Embodiments of systems and methods described herein are designed tomonitor the movement of one or more swallowed pill transducers throughthe human GI tract or digestive system, including the mouth, esophagus,stomach, large and small intestines, colon, and rectum, or any subpartthereof. These systems and methods can include hardware and/or softwarethat can accurately track and record the movement of the pill or pillsas they move through the GI tract to ultimate elimination. An externalsensor system, which may include antennas, enables position trackingand/or flow rate of the pill(s) through the GI tract. The antennas canprovide signals indicative of pill position to a processor, which canperform signal processing to determine pill location, flow rate,motility, or any of a variety of other measurements related to thepill(s). The processor can provide such measurements and information toa display (local to the processor or over a network, such as to acellphone or personal digital assistant (PDA)) for presentation to aclinician, such as a physician, nurse, or other care personnel.

For example, in one embodiment, the systems and methods described hereinuse near field communications to locate a radiating transponder, such asa pill swallowed by a patient. The system can be triggered to turn onand transmit an amplitude shift keyed waveform (or other type ofwaveform) to a set of antennas attached to, coupled with, or near thepatient at roughly known locations. The magnetic field emitted by thetransponder can be measured by the receiving antennas, for example,using principles of mutual inductance. The receiving antennas may betuned specifically to the frequency of the emitting transponder for highsensitivity and high Q. The differential phase and/or time shiftsbetween the antennas can contain sufficient information to find thelocation of the transponder and optionally its orientation relative tobody coordinates. The system can display the location and/or orientationof the transponder and may optionally provide other information aboutthe movement, flow, or other characteristics of pill to assistclinicians with diagnosis.

In addition, in some embodiments, the pill may also include one or moreadditional sensors that output data, which the pill can transmit to thereceiving antennas for processing by the processor. Examples of suchsensors include pressure sensors, pH sensors, temperature sensors,camera(s), salinity sensors, and the like. In other embodiment, however,at least some of such sensors are omitted to reduce the size of thepill, thereby enabling the pill to be small and compact. With its smalland compact shape, the pill can act like food particles and thereforemore accurately represent digestive activity of a patient than currentlarger pill transponders. Further, different size pill transponders thatact like different sizes of food particles can be swallowed by a patientand analyzed by the processor to provide a more comprehensive view ofdigestive activity for presentation to a clinician.

Thus, the systems and methods described herein can provide clinicianswith the ability to identify obstructions, regurgitations, reflux, orother GI conditions that are dangerous to a patient's health and whichare currently difficult if not impossible to monitor in a simple, lowcost, and non-invasive manner. Thus, the systems and methods describedherein can facilitate diagnosing and/or treating numerous diseases andconditions, including, but not limited to, Crohn's disease, bowelstrangulation, neuropathy, diverticulitus, paraplegia-relatedconditions, diabetic gastroparesis, functional dyspepsia, irritablebowel syndrome, epigastric pain syndrome, and post infectious andidiopathic gastroparesis. Further, the systems and methods describedherein can facilitate treating patients with endocrine disorders such ashypo-/hyperthyroidism, pituitary and parathyroid disease, and Addison'sdisease.

III. Example Transponder Monitoring System Overview

Prior to describing transponder location measurements in detail, anoverview of example transponder monitoring system is provided below withrespect to FIGS. 1 and 2. The transponder monitoring system can includea transponder (e.g. pill) and a plurality of antennas. The transpondermonitoring system can track location of the pill with respect to theplurality of antennas. In some embodiments, the transponder monitoringsystem can also automatically track the positions of the plurality ofthe antennas

For example, FIG. 1 shows an embodiment of a physiological monitoringsystem 100. In the physiological monitoring system 100, a medicalpatient 12 can ingest a pill 14, which can be tracked by a patientmonitor 20. The pill 14 can include one or more antennas to transmitsignals as it passes through the GI tract of the patient 12. In anembodiment, the pill 14 transmits a signal in response to a triggersignal from a stimulus antenna 18. The stimulus antenna 18 can bepositioned on the patient or with the patient monitor or in a room. Thepatient monitor 20 can control the operation of the stimulus antenna viaa link 19. The plurality of transceiver units (TU) 16 can also includeone or more antennas to receive the transmitted signals from the pill14. In one embodiment, the system includes 5 TUs. In other embodiments,the system can include 10, 20, 50, or 100 TUs. Increasing the number ofTUs can improve accuracy of measurements, but might require moreprocessing.

The patient monitor 20 can collect the received signals from theplurality of receiving units 16 via a link 17 for processing by one ormore processors 22. Links 17 and 19 can include wired or wireless(Bluetooth, NFC, WiFi or like) communication. The processor 22 canimplement one or more modules for calculating the location of the pill14 in the body of the medical patient 12. The location of the pill 14can be tracked over time and stored in a memory 24 of the physiologicalmonitor 20.

The processor 22 can communicate the processed signals or measurementsto a display 30 if a display is provided. The display 30 can show realtime position (in 2 or 3 dimensions) of the pill in the GI tract of thepatient 12 (as seen more in detail with respect to FIG. 10). In otherembodiments, the position of the pill on the display may be updatedperiodically (e.g. every 1 second, 30 seconds, 1 minute, 5 minutes, 30minutes, etc). The update frequency of the display may be a function ofthe frequency of trigger signals. In an embodiment, the display 30 isincorporated in the physiological monitor 20. In another embodiment, thedisplay 30 is separate from the physiological monitor 20. For example,the physiological monitor 20 can transmit the processed signals over anetwork to the display 30. The physiological monitoring system 100 is aportable monitoring system in one configuration.

In some embodiments, the plurality of TUs 16 are removably attached ator near the body of the patient 12. In certain other embodiments, aframe (not shown) may structurally support the plurality of TUs 16.Accordingly, the patient 12 can be positioned within the framestructure. The TUs 16 may also be affixed on a bed frame. The strengthof the transmitted signals from the pill 14 is inversely proportionalwith distance. Thus, in some embodiments, the TUs 16 are placed in closeproximity to the body of the patient 12 or attached directly to the bodyor to object in close proximity of the patient 12. For example, the TUs16 can be attached to bed sheets or mattresses. The TUs 16 can also beattached to the clothing of the patient, such as a vest or anundershirt. The TUs 16 may be attached, for example, with an adhesive.In some embodiments, the TUs can be sewn or staples with the materials.

FIG. 1B illustrates a block diagram of an embodiment of thephysiological monitoring system 1008. The transceiver units 16 include areceive circuit 142 for receiving signals from the pill 14. In someinstances, the transceiver units 16 may further include a transmitcircuit 144. The transmit circuit 144 and the receive circuit 142 mayinclude an antenna. In some embodiments, the transmit and receivecircuitries can share a common antenna.

In an embodiment, the pill 14 can also include transmit and/or receivecircuitry as described more in detail below with respect to FIG. 2A. Thepill can transmit a signal waveform in response to receiving a triggersignal from the stimulator antenna 18. The signal generator module 154of the physiological monitor 20 can instruct the stimulator antenna 18via the link 19 to transmit the trigger signals. In an embodiment, thesignal generator module 154 can generate the trigger signal waveforms.The trigger signals may be generated over a predefined time interval(e.g. every 1 second, 30 seconds, 1 minute, 5 minutes, 30 minutes, etc).The time interval may have a pattern or can be randomized. In someembodiments, users can control the generation of trigger signal via thephysiological monitor 20. The trigger signals may also be generateddepending on the location of the pill in the patient 12. For example, ina slow moving section of the GI tract, the frequency of triggers signalsmay be lower than in a fast moving section of the GI tract. In someembodiments, the pill may transmit the signal waveform withoutcontinuously requiring external trigger signal. For example, a firsttrigger signal may activate the pill 14 and thereafter the pill 14 mayemit a waveform once every pre-determined time interval for a particularduration. The first trigger signal can be received wirelessly or via aswitch.

The signal collector module 162 of the physiological monitor 20 cancollect the signal waveforms, transmitted by the pill 14, from thetransceiver units 16. The phases of the received signals at TUs 16 mayvary according to the time it takes the transmitted waveform to travelfrom the pill to the TU 16. The travel time (or time of flight) is alsoa function of the distances between the pill and the TUs 16. As such,the phase shifts in the received signals at the first and the second TUmay vary depending on the relative locations of the TUs 16. In someembodiments, the calculator module 152 of the physiological monitor 20can obtain the phase and the amplitude shifts from each of the collectedsignals. The calculator module 152 can calculate the location of thepill 14 in the patient 12 by applying one or more rules, analysis,and/or filtering on the phase and/or amplitude shifts.

In some embodiments, the location of the pill 14 can be calculated fromthe phase differences between the received signals at one or more pairsof the TUs 16. For example, a first TU 16 can receive a transmittedsignal from the pill 14. A second TU 16 can also receive the sametransmitted signal from the pill 14. In certain embodiments, thecalculator module 152 can calculate the location of the pill 14 in thepatient 12 by applying one or more set of rules on the phase differencesbetween the first and the second TUs. The calculator module 152 can alsoapply one or more of rules on a combination of measuredparameters—phases, amplitudes, and phase differences—to calculate thelocation of the pill 14. In some embodiments, the measured parameterscan be obtained from application of signal processing techniques on thereceived signals.

The rules can include linear, non-linear, or a combination of linear andnon-linear set of operations. In some embodiments, an estimator module158 may use one or more linear operations to calculate an estimate forthe location of the pill 14. The calculator module 152 may then use theestimate in one or more non-linear operations to calculate a moreaccurate location for the pill 14. In certain embodiments, a calibrationprocess, described more in detail below, can improve the calculation forpill location by calibrating one or more system parameters, such as pilldesign, TU design, location of the TUs, and the orientation of the TUs.Calibration may be performed with a training data set. In certainembodiments, the physiological monitoring system 100 can adaptivelycalibrate the system parameters while tracking the pill 14 through theGI tract of the patient. Adaptive calibration can include automaticallytracking the location and/or orientation of the TUs 16. As describedabove, TUs may be attached to a patient. Accordingly, the positions andorientations of the TUs 16 may change with patient movement and theshift in TU positions may affect the quality of pill tracking. Adaptivecalibration can be made an instant before the TU locations are used tofind the location of the pill.

Automatically monitoring the positions of plurality of TUs 16 canincrease the accuracy of pill tracking. As described above, TUs 16 mayalso include a transmitter circuit 144 for transmission of a signalwaveform. The signal generator module 154 can generate a plurality oftransmit signals for transmission in a first order from the plurality ofTUs 16. In an embodiment, the signals are transmitted one at a time fromthe plurality of TUs 16. For example, a first TU 16 may transmit a firsttransmit waveform. The plurality of non-transmitting TUs can receive thefirst transmitted waveform, which can be collected by the signalcollector module 162. Subsequently, a second TU 16 may transmit a secondtransmit waveform. In some embodiments, the first and the secondtransmit waveforms are substantially similar. Again, the plurality ofnon-transmitting TUs 16 can receive the second transmit waveform, whichcan also be collected by the signal collector 162. The process cancontinue for each of the plurality of TUs 16. In certain embodiments, asubset of the plurality of TUs 16 may be used to transmit signals. Thesignal collector module 162 can collect, for each transmitted signal,signals received at plurality of the non-transmitting antennas via links17. The calculator module 152 can apply one or more rules, analysis,and/or filtering on the collected signals to calculate the location ofthe plurality of TUs. In some embodiments, the rules can include amodified set of operations from a multilateration analysis.

IV. Example Pill Transponder Embodiments

FIG. 2A illustrates an example block diagram of an embodiment of a pill14 that can be ingested by a patient. The pill 14 can include atransmitter circuit 218 including an antenna for transmitting a signalwaveform. While described herein as a transponder, the pill may be atransmitter without receive functionality in some embodiments. In someembodiments, the pill 14 can transmit a signal waveform in response toan external trigger signal. The receive circuit 216 in the pill 14 canalso include an antenna to receive the trigger signal from the externalstimulator antenna. The receive circuit 216 and the transmit circuit 218may share an antenna. The antenna may be referred to or be configured asa loop antenna. The antenna may also be referred to or be configured as“magnetic antenna” or an induction coil. The antenna may also include acoil of a type that can wirelessly output or receive wirelesscommunication signals. In some embodiments, the antennas may alsowirelessly output or receive power. The pill can also includecommercially available or custom RFID tag. In some embodiments, the pillcan operate in a passive mode of operation. In the passive mode ofoperation, the pill may not require a battery or power storage device220. The external trigger signal can provide sufficient power to thepill for transmitting the signal waveform. The pill may also operate inan active mode or battery-assisted passive mode, requiring an on-boardbattery or a power storage device 220. In the battery-assisted passivemode, the on-board battery 220 can be smaller than in the active mode.

In the active mode, the pill 14 can be configured to periodicallytransmit the waveform signal. The pill 14 may transmit the signals basedon a predetermined time intervals. For example, after receiving anexternal stimulus (before or after ingesting the pill), the pill cantransmit a signal waveform over a time interval (e.g. every 1 second, 30seconds, 1 minute, 5 minutes, 30 minutes, etc). The pill may alsotransmit the signal waveform continuously but that may increase thepower duty cycle. In some embodiments, the external signal can be amechanical switch. The switch may be turned on before ingesting the pillcausing it to periodically transmit a signal waveform. The on-boardbattery may provide sufficient power for the pill to transmit thesignals over a span of several days.

In the passive or battery-assisted passive mode, the pill 14 cantransmit a signal waveform in response to receiving the trigger signal.The circuitry in the pill can activate in response to the trigger signaland transmit a signal waveform. The pill 14 can then go into a passivestate until the next trigger signal is received. In certain embodiments,the physiological monitor 20 can control the generation of triggersignals and transmission from the external stimulus antenna. The triggersignals may be generated over a time interval, for instance, every 1second, 30 seconds, 1 minute, 5 minutes, 30 minutes, etc.

The waveform characteristics of the transmit signal can be stored in amemory 220 of the pill 14. The waveform characteristics can also bedefined by the circuit elements of the transmit circuitry 218. In someembodiments, the transmit waveform can correspond to the characteristicsof the trigger signal. The transmit waveform can also be modulated toreduce interference from external signals. Some of the modulationtechniques can include Amplitude Shift Keying, Phase Shift Keying, orFrequency Shift Keying. In an embodiment, the duration of the transmitwaveform is 1 ms. In other embodiments, the duration of the transmitwaveform can be 0.1 ms, 10 ms, 100 ms. The pill may also the transmitthe signal continuously.

The frequency characteristics of the transmit waveform can depend onseveral parameters. For example, at higher frequencies of more than 20MHz, absorption of the signal waveform by the body tissue and organs maybecome significant. Furthermore, far field circuit antennas, may requireprecisely tuned GHz circuitry resulting in complex and expensive system.Near field coupling can allow for simpler electronics and communicationvia lower frequencies in the range of MHz. In an embodiment, thefrequency of the transmit waveform is approximately 13.56 MHz which ispart of the industry, scientific, and medical (ISM) radio band. At thisfrequency, there may be some absorption, but the transmit waveform canpass through 10 cm of body. In another embodiment, the frequency of thetransmit waveform is approximately 125 KHz. In yet another embodiment,the frequency of the transmit waveform is 6.8 MHz. At lower frequencies,the absorption from the body may be significantly reduced. In otherembodiments, any frequency below 20 MHz may be used to reduceabsorption. Frequencies equal to or higher than 20 MHz may also be usedin certain embodiments. The frequency may also depend on the powerconstraints of the emitted waveform. For example, there are limits onpower emissions of signals defined by industry standards and regulatoryagencies to protect human body. Accordingly, in one embodiment, thepower of the transmitted waveform is on the order of microwatts, ormilliwatts, or 3 watts or less, or some other value.

FIG. 2B illustrates a cross-section 250 of an embodiment of a pilltransmitter 14. The electronics in the pill can be encapsulated with amaterial that is suitable for ingestion, for example,polytetrafluoroethylene (PTFE). The size of the pill 14 can varydepending on the size of the circuitry, for example, the size of thebattery 220. In an embodiment, the size of the pill 14 is 5 mm×12 mm.For a pill with a smaller battery, the size can be reduced to 4 mm×6 mmcapsule. In an embodiment, the antenna includes a ferrite core and has amicro rod design.

One benefit of the shape and size of the pill in certain embodiments isthat the pill can be small enough that it acts like food. Thus, the pillcan move with food and therefore mimic the motility or GI problems thatfood is having in the patient's body. The size of the pill is small incertain embodiments because the pill may not have a bulky camera as inother existing pill designs. Existing pills from other manufacturers canactually be so large that they become obstructions themselves. Incontrast, in certain embodiments, the pill described herein can be about6 mm in size or less. Alternatively, the pill may be about 1.2 cm insize or less, or a slightly greater size. The smaller size pill can movewith smaller sized bits of food, while the larger sized pill can movewith larger bits of food. Different sized pills can therefore be used todiagnose or analyze different illnesses. In fact, different sized pills(including more than 2 different sizes) can be swallowed by the patientand tracked at the same time to track both small food movements andlarger food movements. Any number of pills may be swallowed and trackedat one time, for example, up to 5 pills, or up to 10 pills, or up to 24pills, or up to 48 pills. In one embodiment, detecting solely motilitycan be accomplished using a single pill, but also detecting obstructionscan be accomplished using multiple pills.

FIG. 2C illustrates a model circuit diagram 270 of an embodiment of apill 14. The inductor L_(p) in the conception circuit diagram can be 1μH and the capacitor C_(p) can approximately be 150 pF such that1/√L_(p)C_(p)=2π×13.0 MHz. The R_(pi) in series with the inductor canrepresent the internal wire Ohmic resistance, presumably only a fewOhms. In some embodiments, the model can include a capacitor in serieswith the RLC circuit. Resistor R_(p) can represent the eddy current andhysteresis losses in the inductor core. In an embodiment, R_(p) is inparallel because that better models the measured frequency dependencewhen driven with a sweep frequency. The R_(p) value can be greater than1 kΩ. In the model, the circuit is driven with an oscillator voltagesource V_(o) at some frequency ω. That forces a prescribed voltageacross the parallel RLC.

However if an external magnetic field penetrates the area of the entirecircuit, or of just the inductor L_(p), it can induce an additional emfacross L_(p)-R_(pi) and so across R_(p) and C_(p). Such a magnetic fieldis provided by mutual inductance M from the currents in the nearby TUantenna circuits as illustrated in FIG. 2C by the dashed source on theright, marked M and “+” to indicate its emf is added to Vo. I_(p) is thetotal current drawn from the voltage source by the pill circuit. I_(pL)is the current through the pill inductor L_(p).

In one embodiment, the pill can be modeled as a radiating magneticdipole. In another embodiment of the pill, the pill can radiatesequentially through three orthogonal dipole directions, similar to aphased magnetic array (not shown), which gives an almost uniform fieldfor all TUs to measure. Examples of pills including orthogonal dipolesare described in detail in a pending application Ser. No. 14/520,219,titled “Nearly Isotropic Dipole Antenna System,” filed on Oct. 21, 2014,which is incorporated by reference herein in its entirety. The processfor tracking location of a pill transmitter described below can beextended to a pill having multiple antennas. For example, if the pillhas three antennas, the receiving antennas may receive three signalscorresponding to each of the pill antennas. Both embodiments can be usedto find the location of the pill using the analysis described herein.

V. Transceiver Units

FIG. 3 illustrates an embodiment of a TU system 300 including aplurality of TUs connected to a communication box 301 via one or morelinks 310. The links can include wired or wireless type connections. Forthe wired connections, the links 310 can be arranged a single cable. Thecable may be also be shielded. As described above, the TUs 302-306 caninclude one or more antennas for receiving or transmitting signals. Inan embodiment, the communication box 301 can include a patient monitor20. In another embodiment, the communication box 301 can include amobile device that collect the received signals from the TUs andtransfer the signals to the patient monitor 20. The transfer of thesignals from the communication box 310 to the patient monitor 20 can bevia a (wired or wireless) network. Accordingly, in one embodiment, thepatient can be mobile without carrying the patient monitor.

The antenna may be referred to or be configured as a loop antenna. Theantenna may also be referred to or be configured as “magnetic antenna”or an induction coil. The antenna may also include a coil of a type thatcan wirelessly output or receive wireless communication signals. In someembodiments, the antennas may also wirelessly output or receive power.

VI. Example Pill Location Process

FIG. 4 illustrates an embodiment of a process 400 for calculating thelocation of a pill in the patient 12. This process can be implemented bythe system 100 described herein. In particular, each of these processescan be implemented by one or modules in the patient monitor 20 describedabove. Advantageously, in certain embodiments, these processes canenable monitoring of a pill as it moves through the GI tract of apatient. In some embodiments, the location of the TUs and the couplingcoefficients between the antennas are calculated prior to calculatingthe location of the pill.

Referring specifically to FIG. 4, at block 410, the signal generatormodule 154 can generate a trigger signal that may be transmitted from anexternal stimulus antenna 18. The pill 14 can receive the trigger signaland in response transmit a signal waveform. The plurality of TUs 16 canreceive the signal waveform transmitted from the pill 14. In someembodiments, the pill 14 can generate the transmit signal withoutrequiring a trigger signal. At block 412, the signal collector module162 can collect the received signal waveforms from the plurality of TUs16. The calculator module 152 can analyze the collected waveforms tocalculate a first set of measurements at block 414. In an embodiment,the measurement module of the patient monitor 20 can calculate relativephase (or phase shifts) and amplitude measurements for each of thecollected signals. In certain embodiments, the measurement module canalso measure the phase differences between one or more pairs ofcollected signals. Then, at block 416, the location calculator modulecan calculate the location of the pill by applying a first set of rules,analysis, or filtering on the measurements.

The first set of rules can include linear, non-linear, or a combinationof linear and non-linear set of operations. In an embodiment, the firstset of rules can be applied to an electromagnetic coupling model of thesystem described more in detail below. In certain embodiments, anestimator module 158 can calculate a first estimate of the pilllocation. The location calculator module 152 can use the first estimateas a starting set of values to solve for the location of the pill. Forexample, in certain embodiments, a linear set of operations (e.g.multivariate linear regression) can be used to calculate the locationestimate and then the location calculator module can use non-linearoperations (e.g. Levenberg-Marquart analysis) to refine the estimatedvalue. As the pill moves through the body, location state vector modelsmay be used to further improve the accuracy of tracking. For example, aMarkov chain, Kalman filter, or a combination of Markov chain and Kalmanfilters can be used to improve tracking. Other tracking filters may alsobe used. A pill trajectory can be calculated by taking derivative of thepill locations. The trajectory may be shown on the display 30.

The location calculator module 152 can use one or more models tocalculate the location of the pill. For example, the calculator module152 can use electromagnetic coupling model which will be described morein detail below. The location calculator module can also usemultilateration analysis on the collected signals for calculating pilllocations. The multilateration analysis can be used independently or inconjunction with the electromagnetic coupling model. The locationcalculator module 152 can take into account secondary coupling effectsdescribed below to refine the measurements. In some embodiments, thepill can be accurately located within a 1 cm error margin in threedimensions.

In some embodiments, the location calculator module 152 can calibratethe system by measuring initial system parameters for use in one or moremodel calculations. The system parameters can include pill geometry,location of the TUs, orientation of the TUs, and other related inherentproperties of the system. The location calculator module can apply thesystem parameters in calculating the location of the pill. The initialcalibration (training set) process is described in more detail withreference to FIGS. 9A and 9B. Further, dynamic calibration can modifythe initial system parameters by automatically measuring the location ofTUs over time as described below.

VII. Example Dynamic Transceiver Antennas (TUs) Position CalculationProcess

As described above, the plurality of TUs 16 can be affixed, coupled toor placed in proximity with the patient 12. The location and theorientation of TUs may change as the patient moves during the pilltracking process which may run on over several hours or days. Accuratelytracking the location of TUs can improve the pill tracking because thepill is tracked as a function of TU coordinates. A translator module 156can convert the pill location from the TU coordinates to bodycoordinates for display on a screen. FIG. 5 illustrates an embodiment ofa process 500 for calculating TU locations. This process can beimplemented by the system 100 described herein. In particular, each ofthese processes can be implemented by one or modules in the patientmonitor 20 described above.

Referring specifically to FIG. 5, at block 510, the signal generatormodule can generate a transmit signal for transmission from a first TUin the plurality of TUs 16. The non-transmitting TUs in the plurality ofTUs 16 can receive the transmitted signal from the first TU. The signalcollector module can collect the received signals from thenon-transmitting TUs at block 512. The calculator module can process thecollected signals and calculate a first set of measurements. The firstset of measurements can include one or more of the following: timedifference measurements, relative phase shifts measurements, phasedifferences or amplitude shifts. In some embodiments, the collectedsignals might be stored for later processing. Thereafter, the processcan be repeated for other TUs that have not yet been used fortransmitting signals. Once the system has cycled through all or a subsetof the plurality of TUs, the calculator module can calculate thelocation of TUs from all the collected signals and measurements at block518. In some instances, transmission from one or more may TUs may berepeated. In yet more embodiments, a subset of TUs from the plurality ofTU's are used. The location calculator module can apply rules, analysis,or filtering on the set of collected data to calculate the locations.The rules can include a set of linear, non-linear, or a combination oflinear and non-linear operators.

In some embodiments, the positions of the TUs can be automaticallycalculated by a multi-multilateration (MML) process. The MML processbuilds on the basic idea of multilateration. In the MML process, thephase differences found by sequencing through the TUs can be related tothe time difference of arrival after correction for all secondary phaseinteractions are accounted for. In another embodiment, the multivariatelinear regression is used to find the locations without regard tocorrecting phases from secondary interactions, but by forming a trainingset that has the secondary interactions included in the training dataset. Both embodiments are further discussed in the following paragraphs.

VIII. Multi-Multilateration

Multilateration analysis can be used to calculate a location of atransmitting antenna based on signals received at the plurality ofreceivers. Multilateration analysis relies on the principal of timedifference of arrival (TDOA) of a signal from the emitter at four ormore transceiver sites. A multi-multilateration technique can be used tolocate plurality of transmitting antennas in relative transmittercoordinates.

FIGS. 6A and 6B illustrates an embodiment of a process 600 forcalculating locations of the TUs using MML. This process can beimplemented by the system 100 described herein. In particular, each ofthese processes can be implemented by one or modules in the patientmonitor 20 described above. The TUs can be measured in three dimensionsas they are placed on or near the body.

Referring to FIG. 6A, at block 610, the TUs can be placed at variouslocations on or near the body of the patient. In an embodiment, thedistances between TUs can be constrained and the normals of the antennasmay be known as shown in block 612. The variation of the signal is aweak function of the normal vector and a general knowledge of the normalvector relative direction is adequate to find the TU locations. Thesignal generator can generate a plurality of transmit signals fortransmission from the plurality of TUs, at block 620, as described withrespect to FIG. 5 for dynamic antenna position calculation. At block614, the TUs can emit the transmit signals. The transmit signals can beemitted one at a time from each TU. The transmit signals may have verywell defined ASK (Amplitude Shift Key) frequency and phase. Thefollowing process is described with 5 TUs. In other embodiments, thesystem may include different numbers of TUs. At block 616, the signalcollector module can collect the received waveforms from the pluralityof TUs 16 also as described with respect to FIG. 5. The calculatormodule can then obtain a first set of measurements (e.g. time delay ofarrival, amplitude, or relative phase or phase shift) from the collectedsignals at block 618, 622, 624, and 626.

At block 626, the calculator module calculates x, y, and z coordinatesusing the multilateration equations as shown below. The number ofequations can depend on the number of TUs. For 5 TUs, there are 15unknown coordinate positions. In one embodiment, the normal positions ofthe antennas can be approximately known. In solving for the locations,one of the TUs (TU1) can be set as the origin (0,0,0) to make the matheasier. A second TU (TU2) can be placed at a known position on the body,for example at vertebra C7. TU2 can be assigned to have coordinate of(X2,0,0). This can define the direction of the TU centric X-axis. TheY-axis can be defined as normal to X-axis and in the plane formed fromthe origin, C7, and a third TU (TU3). The TU3 coordinates then are(0,Y3,Z3). An example TU-centric coordinates are shown in FIG. 11A.Thus, the TU centric coordinate system can be defined such that five TUcoordinates are known, i.e. the X1, Y1, Z1, Y2, Z2, X3 are all zero. Theother ten coordinate positions are unknown and must be found by solvingthe ten equations from the ten phase difference measurements between theTU pairs (TU1-TU2, TU1-TU3, TU1-TU4, TU1-TU5, TU2-TU3, TU2-TU4, TU2-TUS,TU3-TU4, TU3-TU5 and TU4-TU5). Accordingly, there are ten equations withten unknowns, assuming that the antenna normals are known at leastroughly. In an embodiment, the antenna normals are known from parts ofthe body they are attached to relative to the body coordinates. As anexample, for antennas placed on the top rib cage facing toward the back,the normals are pointing toward the spinal column, and antennas on thesides are perpendicular to the spinal column. This relative normaldirection knowledge can be adequate to locate the antennas and thus thepill. The equations are described below. At block 630, the calculatormodule can solve the 10 unknowns using a set of rules. The set of rulescan include linear, non-linear, or a combination of linear andnon-linear operations. In some embodiments, the calculator module canrun numerical analysis techniques to measure the locations from the setof equations.

Example equations to be solved to find the antenna orthogonalcoordinates can include those in Table 1, below. The coordinate systemof the TUs can be translated, rotated, or distorted.

TABLE 1 Index m n k Ref r  1 3 2 1 0  2 4 2 1 0  3 4 3 1 0  4 2 1 0 2  53 1 0 2  6 3 2 0 1  7 4 1 0 2  8 4 3 0 1  9 4 3 2 0 10 4 2 0 1

Table 1 is an example table of the indices for the parameters in thenon-linear simultaneous equations being solved to find the coordinatesof antennas in antenna-centric coordinates using themulti-multilateration process. The equation 1 (below), for example, canrepresent the time delay of arrival, TDOA, between antenna 3 and 2coming from transmitter 1, relative to antenna 0. The position of theantennas can be found in antenna-centric coordinates.

The indices of Table 1 can be applied to Equation 1 shown here:

$\begin{matrix}{0 = {{v\tau_{mnk}} - {v\tau_{rnk}} + \frac{\left( {S_{nk}^{2} - S_{mk}^{2}} \right)}{v\tau_{mnk}} - \frac{\left( {S_{nk}^{2} - S_{rk}^{2}} \right)}{v\tau_{rnk}}}} & (1)\end{matrix}$

Where the indices of m, n, k and r can take on the values given inTable 1. The S_(nk) values can represent the distances of the antenna kto antenna n. The values of v*□_(mnk) can be the TDOA distance derivedfrom the ping pulse with velocity v coming from antenna k and crossingthe antenna n and crossing antenna m. This time difference can be foundfrom the homodyne relative phase time difference of the wave measured atm and n. The calculator module can use signal processing techniques(such as cross-correlation) to measure phase differences. The timedistance delay can be a function of the wavelength, capture time, wavepropagation delay and noise in the devices.

For five transceivers, there can be 10 equations and 10 unknowns. Oncethe v*τmnk (TDOA distances) from some or all antennas is known, thesolution location coordinates can be found by using a conjugate gradientnon-linear process to find the best solution of Equations (1). Thestarting values can be given as the initial position estimates on theantenna platform and may be roughly known.

TABLE 2 Example Initial conditions, givens, unknowns and assumptions forsolving equations in Table 1 Unknowns Givens Assumptions x_(m), y_(m),z_(m) x₀ = 0,y₀ = 0,z₀ = 0 origin at e.g. 105, where origin -- ant. 105origin Y axis in plane 1 < m < 4 x₁ = x₁, y₁ = 0, z₁ = 0 of positionvectors given as the 106 x₀, x₁,x₂ x₂,y₂,0 given as 103 Measurement: V *□_(mnk) 0 < m < 4, 10 relative TDOAs 0 < n < 4, between m and n coming k= 0,1,2 in pairs from ping from k Trigger time of ping The signalcrosses the is known receiver within one cycle within psec. of thepinger periodIn an embodiment, after finding the TU locations, the location of thepill can be found by using direct multilateration. The calculator modulecan implement solving the following set of equations or the like (formultilateration):

$\begin{matrix}{{0 = {{xA}_{m} + {yB}_{m} + {zC}_{m} + D_{m}}}{A_{m} = {\frac{2x_{m}}{v\tau_{m}} - \frac{2x_{1}}{v\tau_{1}}}}{B_{m} = {\frac{2y_{m}}{v\tau_{m}} - \frac{2y_{1}}{v\tau_{1}}}}{C_{m} = {\frac{2z_{m}}{v\tau_{m}} - \frac{2z_{1}}{v\tau_{1}}}}{D_{m} = {{v\tau_{m}} - {v\tau_{1}} - \frac{x_{m}^{2} + y_{m}^{2} + z_{m}^{2}}{v\tau_{m}} + \frac{x_{1}^{2} + y_{1}^{2} + z_{1}^{2}}{v\tau_{1}}}}} & (2)\end{matrix}$

where the x_(m)'s, y_(m)'s, and z_(m)'s form the m TU position vectorsfound from the multi-multilateration calculation (described above) forexample with reference to antennas 302 to 306. The origin can be atpoint 305 on the antenna coordinate system.

In some embodiments, the calculator module can correct for second ordereffects. Each of the TUs can interact with all other antennas attachedto the body. This can result in a secondary coupling effect. Thesecondary coupling effect can change the amplitude and phase of themeasurements in all antenna TUs. The second order (or secondary)coupling can be calculated from the measured amplitudes of each antenna.A solution to a set of equations shown in the second order effectssection below can be used to find the secondary coupling between allTUs. In some embodiments, the phase shift from all the secondarycouplings can be nearly a fixed constant. The phase shift from thesecondary coupling was calculated to be 76 degrees (in addition to thephase shift from the primary TU) from a model calculation using 4 TUs.The true phase shift from one antenna to another without the phaseinteractions from all the other measured phase shifts can then be found.The true phase shifts can then directly correlate to simple time offlight measurements from one antenna to another and can be used inEquation 1. The speed of the waveform can be calculated from the knownfrequency and wavelength of the transmit waveform.

IX. Transponder Location System Overview

FIGS. 7A and B illustrate an example process 700 for tracking locationof the pill 14 ingested by a patient. The process 700 can be dividedinto two sub-processes. Sub-process A (FIG. 7A) can include steps fordynamically finding the location of TUs as described with respect toFIG. 5. In some embodiments, Sub-process A is performed before each pilllocation measurement described in sub-process B (FIG. 7B). Sub-process Bcan include steps for locating the current position of the pill asdescribed with respect to FIG. 4.

The process 700 may use initial calibration measurements represented byblocks 710 to 714 to calculate locations in subprocess A and/or B. Forexample, using calibration process described below, the system can storeinput parameters in the memory of the patient monitor. Input parameterscan include initial estimate of pill location (e.g. Z-axis distance fromorigin in antenna coordinate system) obtained by comparing the measuredvalues (e.g. phase differences) with the previously stored measurements.Input parameters can also include betas used in the electromagneticcoupling model for locating the pill. The location of the TUs can becalculated in antenna-centric coordinates using the process described inblocks 716 to 722. Once the locations of the TUs are measured,sub-process B as shown in FIG. 7B can be used to calculate the locationof the pill. The estimator module can calculate an estimate from thecalibration process or previously calculated pill location. Thecalculator module can use the estimated value in a non-linear analysisto refine the location. The calculator module can implement trackingfilters at blocks 750 and 752.

At block 754, the calculator module can check whether the locationcalculation for the pill is converging. Sometimes, the locationestimates may get stuck in local minima and in that case the system mayrecalculate the location from block 748. If the location estimate hasconverged, the translator module can convert the antenna-centriclocation to body centric coordinates and display the location of thepill on a monitor as shown in FIG. 10. The location value can be savedin the memory of the patient monitor at block 756. At block 762, thecalculator module can calculate a pill trajectory by calculating aderivative of the pill locations. At block 760, the process might beconcluded or repeated as the pill moves through the GI tract of thepatient. At block 760, the pill location process may start over again atsub-process A. As described above, finding the next pill location may bedone continuously or every 1 second, 30 seconds, 1 minute, 5 minutes, or30 minutes.

X. Models/Rules

The following models can be used to calculate pill locations using themeasurements obtained from one or more processes described above.

a. Electromagnetic Coupling Model (Multivariate Linear Regression)

Mutual inductance represents a measure of coupling between twoinductors. At small distances and selective wavelengths, the couplingbetween two antennas can be almost entirely be magnetic. Magnetic fieldscan easily pass through the body tissue without significantinterferences. Mutual inductance can be a function of the geometricconfiguration, orientation and position of (distance between) theantennas. Mutual inductance can also be proportional to induced currentin a second antenna and its phase from a changing current in a firstantenna. Furthermore, in a system where plurality of antennas areconfigured to receive a signal from a common source, the phasedifferences between the signals received from the common source at theplurality of antennas can also be a function of mutual inductance. Forexample, the phase difference between received signals at a first TU anda second TU, where the signal was transmitted from a pill 14, can be afunction of the mutual inductance.

As described above, with respect to FIG. 4, the one or more modules ofthe physiological monitor 20 can obtain phase and phase differences froma set of collected signals. Antenna geometric configuration can also bemeasured. In an embodiment, the antennas are coil-type antennas with aferrite core. The mutual inductance between two antenna coils isfunction of the number of turns, area, relative permeability of thecore, and correction factor (aspect ratio of the ferrite core(length/diameter) and the fraction of the core length occupied by thewire turns) of each of the two antennas. The mutual inductance is also afunction of the distance (r) taken from the two antennas and theorientation of antennas. After much math later (shown in Appendix A),the mutual inductance M_(Tj) between an antenna pill coil T and antennacoil 2 can be modeled by the following equation:

$\begin{matrix}{{M_{Tj}\left( {\overset{Ur}{X_{Tj}},\overset{)}{N_{T}}} \right)} = {K_{T}\mu_{rT}N_{j\_ turns}A_{T}K_{j}\mu_{rj}N_{T\_ turns}A_{j}\frac{{3\;\cos\;\theta\;\sin\;\theta\;{\hat{z} \cdot \hat{\rho}}} + {\left( {{3\;\cos^{2}\theta} - 1} \right){{\hat{z}}^{\prime} \cdot \hat{z}}}}{r^{3}}}} & \left( {{Equation}\mspace{14mu} 3} \right)\end{matrix}$

The angular and vector components in the above equation correspond tothe B-field vector dotted into the receiver area vector of the antennas.

The strength of the B-field is proportional to the pill area vectornormal, number of turns and other circuit details. Solving for theangular and vector components can enable finding the location of thepill.

In Equation 3,

${\overset{ur}{X}}_{Tj}$

is the position vector of the TUj in the pill centric coordinates (thatis the center of the pill is the origin). The normal of the pill dottedinto the normal of the receiver is given by

and dot product of the cylindrical coordinate B-field component with thereceiver normal is given as

·{circumflex over (ρ)}, in the pill centric coordinates.

The phase difference between the received signals at TU_(i) and TU_(j)can be a function of mutual inductance. For instance, the coupling(mutual inductance) between the pill and a first TU can be affected bythe presence of other TUs because the pill can couple with multiple TUssimultaneously. In one embodiment, the effect of multiple TU couplingcan be modeled with the phase differences between TUs. That is, thephase difference between TU_(i) and TU_(j) might be a function of thecoupling between TU_(j) and the pill. This relationship can be modeledas a linear, non-linear or a combination of linear and non-linearfunctions. In one embodiment, the phase difference can be modeled asproportional to the mutual inductance (from Equation 3) to the firstorder as shown in Equation 4 below. In other embodiments, higher orderpolynomials can also be included in the model.

In the simplest embodiment implementation, the phase differences can bemodeled as a linear function of the calculated phase difference of theTU_(i) and TU_(j). This phase shift is based on the calculated mutualinductance between TU's i and j. This model with no corrections forsecondary effects is given as

$\begin{matrix}{{\Delta\;{P_{k,{ij}}\left( {{\overset{ur}{X}}_{k,{Ti}},{\overset{ur}{X}}_{k,{Ti}},{\overset{r}{N}}_{k,T}} \right)}} = {\beta_{0} + {\beta_{1}{{\Delta\phi}_{ij}\left( {{\overset{ur}{X}}_{k,{Ti}},{\overset{ur}{X}}_{k,{Ti}},{\overset{r}{N}}_{k,T}} \right)}}}} & (4)\end{matrix}$

Where

${\Delta\phi}_{ij}\left( {{\overset{ur}{X}}_{k,{Ti}},{\overset{ur}{X}}_{k,{Ti}},{\overset{r}{N}}_{k,T}} \right)$

is the phase difference calculated from the uncorrected model fortraining set point k, pill to antenna i and antenna j. The phasedifference between antenna TU_(i) and TU_(j) is then found is:

$\begin{matrix}{{\Delta\;{\phi_{ij}\left( {{\overset{ur}{X}}_{k,{Ti}},{\overset{ur}{X}}_{k,{Ti}},{\overset{r}{N}}_{k,T}} \right)}} = {{\phi_{Ti}\left( {M\left( {{\overset{ur}{X}}_{Ti},{\overset{r}{N}}_{T}} \right)} \right)} - {\phi_{Tj}\left( {M\left( {{\overset{ur}{X}}_{Tj},{\overset{r}{N}}_{T}} \right)} \right)}}} & (5)\end{matrix}$

This phase difference then becomes the independent value for aregression analysis. For each measurement of the training set position,the phase difference is calculated in a first order model. There are

${c\begin{pmatrix}n \\2\end{pmatrix}} = C_{2}^{n}$

combinations of phase differences. For n=4 antennas, there are m=1 to C₂⁴, (m=1,6 for four TUs) phase differences; for k training set points,the phase differences are labeled here as

${\Delta\;{P_{k,{ij}}\left( {{\overset{ur}{X}}_{k,{Ti}},{\overset{ur}{X}}_{k,{Tj}},{\overset{r}{N}}_{k,T}} \right)}},$

where k=1 covers all training set points, and ij pairs m=1,6. The designmatrix then is given by Equation 4.

The βs (betas) represent the strength parameters of the phasedifferences for various locations of the pill. The

$\Delta\;{\phi_{ij}\left( {{\overset{ur}{X}}_{k,{Ti}},{\overset{ur}{X}}_{k,{Ti}},{\overset{r}{N}}_{k,T}} \right)}$

is a function of system parameters, (e.g. pill geometry, location ofTUs, pill location, pill normal, etc.). It is the calculated phasedifference of antenna pair ij at point k in the training set. Asdescribed above with respect to FIG. 5, a calibration process can beused to solve for the betas. Equation 5 can rewritten in a matrix formfor the plurality of phase difference between TUs as shown below:

$\begin{matrix}{{\begin{pmatrix}{\Delta P_{1,12}} & {\Delta P_{1,13}} & \ldots & {\Delta P_{1,34}} \\{\Delta P_{2,12}} & {\Delta P_{2,13}} & \ldots & {\Delta P_{2,34}} \\\vdots & \vdots & \vdots & \vdots \\{\Delta P_{k,12}} & {\Delta P_{k,13}} & \ldots & {\Delta P_{k,34}}\end{pmatrix} = {\begin{pmatrix}1 & {{\Delta\varphi}_{1,2}\left( {{\overset{\rightharpoonup}{X}}_{1,{T\; 1}},{\overset{\rightharpoonup}{X}}_{1,{T\; 2}},{\hat{N}}_{1,T}} \right)} & \ldots & {{\Delta\varphi}_{1,13}\left( {{\overset{\rightharpoonup}{X}}_{1,{T\; 3}},{\overset{\rightharpoonup}{X}}_{1,{T\; 4}},{\hat{N}}_{1,{T\; 6}}} \right)} \\1 & {{\Delta\varphi}_{1,2}\left( {{\overset{\rightharpoonup}{X}}_{2,{T\; 1}},{\overset{\rightharpoonup}{X}}_{2,{T\; 2}},{\hat{N}}_{2,T}} \right)} & \ldots & {{\Delta\varphi}_{1,13}\left( {{\overset{\rightharpoonup}{X}}_{1,{T\; 3}},{\overset{\rightharpoonup}{X}}_{1,{T\; 4}},{\hat{N}}_{2,{T\; 6}}} \right)} \\\vdots & \vdots & \vdots & \vdots \\1 & {{\Delta\varphi}_{1,2}\left( {{\overset{\rightharpoonup}{X}}_{k,{T\; 1}},{\overset{\rightharpoonup}{X}}_{k,{T\; 2}},{\hat{N}}_{k,T}} \right)} & \ldots & {{\Delta\varphi}_{3,4}\left( {{\overset{\rightharpoonup}{X}}_{k,{T\; 3}},{\overset{\rightharpoonup}{X}}_{k,{T\; 4}},{\hat{N}}_{k,{T6}}} \right)}\end{pmatrix}\begin{pmatrix}\beta_{0,1} & \beta_{0,2} & \; & \ldots & \beta_{0,6} \\\beta_{1,1} & \beta_{1,2} & \; & \ldots & \beta_{1,6} \\\vdots & \vdots & \; & \vdots & \vdots \\\beta_{k,1} & \beta_{k,2} & \vdots & \ldots & \beta_{k,6}\end{pmatrix}}},} & (6)\end{matrix}$

Where the design matrix is defined at all of the k training set pointsfor each of the six phase differences when four antennas are receivingthe signal.

In Equation (7), the phase difference between i and j is modeled aslinear and first order in the calculated phase difference for the pillat location k to the six antenna receiver pairs i and j when only fourantennas are present. This equation results in six equations with kpoints to be fit by the six equations. The beta matrix is then k+1 by 6.The design matrix is k by 7.

The size of the matrix depends on the number of TUs in the system 100.The design matrix, i.e. the left hand matrix on the right hand side ofequal sign is called M. The □□factors are contained in matrix

ΔP=Mβ  (7a)

β=(M ^(T) M)⁻¹ M ^(T) MΔP  (7b)

Equations 7a and 7b are written in matrix form. Equation 7b shows commonmatrix operations (e.g. transpose and inverse). The equations willalways find a solution if the (M^(T)M)⁻¹ is invertible. For the casewhere many data points are used to build the design matrix, it will beinvertible. In the calibration embodiment, the pill positions will beknown as discussed with respect to FIGS. 8A and 8B. The ΔP (phasedifferences) can also be measured. The mutual inductance,

$M_{Tj}\left( {{\overset{ur}{X}}_{Tj},{\overset{)}{N}}_{T}} \right)$

and thus the phase difference values can also be calculated by pluggingin the pill parameters and TU locations in Equation 3. The TU locationscan be fixed or can be measured dynamically through multilateration or asimilar electromagnetic coupling model described with respect tolocating the pill. One or more rules, including linear, non-linear, or acombination of linear and non-linear operations can be used to calculatethe betas. In one embodiment, a linear regression analysis can be usedto calculate the betas. In other embodiments, one or more numericalestimation techniques can also be used to solve for betas. In someembodiments, the calibration (described below) can be done once beforethe pill tracking. In certain embodiments, the calibration process canbe dynamically performed while tracking the pill as it passes throughthe GI tracts. For example, a calibration calculation can be conductedbefore every pill location measurement. The positions of TUs can beadaptively calculated as they might change with patient movement.

After solving for betas, the location of the pill can be calculatedusing one or more rules including linear, non-linear, or a combinationof linear and non-linear operations. In one embodiment, the followingset of rules can be applied:

ΔP=Mβ  (8)

Residual=ΔP−Mβ  (9)

In Equation 9, the betas are known from the calibration process and thephase differences ΔP between the TUs can also be measured. For 5 TUs,there are 10 measured phase differences. Furthermore, most of theparameters (number of turns, peremeability etc.) for calculating mutualinductance are also known. Thus, the pill position (X_(Tj)) andorientation (

) are the unknowns in Equation 9. One or more numerical methods can beused to solve for the unknowns. The system approaches towards a solutionas the residual approaches towards zero. In an embodiment, a linear or anon-linear regression analysis can be used to solve for the unknowns. Inaddition, sum of least squares error fit may also be used to calculatethe unknowns. For example, an estimator module 158 implemented in themonitor 20 can first calculate an estimate by a method of least squaresor linear regression. The estimator module can also use non-linearoperations. The calculated estimate can then be used in other numericalmethods to refine the estimate. For example, in one embodiment,Levenberg-Marquardt method is used to refine the estimate.

In addition, the pill estimate can be refined by using the previouscalculated or known pill location. The location calculator and estimatormodule can also use state transition and statistic models to refine pilllocation calculations. In one embodiment, the modules apply Markov chainalong with Kalman filter to track the pill locations. In Markov chain,the next state (eg. next pill location) can depend on the previous state(eg. previously calculated pill location) and there is a probabilityassociated with the transitions. Kalman filter can, for example, take anestimate calculated from the laws of physics to contain the measuredvalue. For example, from the previous pill locations and velocity, thenext set of pill locations can be estimated. However, because of noiseand other interference, the pill location process may return animprobable value. Markov chain and Kalman filter can provide statisticalprobabilities for the correct location of the pill. The location of thepill can be tracked in three dimensions.

b. Second Order Coupling Correction—1

The second order effects can be used to correct the measured phases tobe equivalent to the TDOA in the multi-multilateration analysis describeabove. The second order effects can take the phase difference curveversus calculated phase shift and transform it to a linear curve. Thus,the phases corrected for TU coupling can be used to improve locationestimate. The model to estimate phase uses TU and pill circuit modelsand locations geometry along with the coupling between each TU. Thephase at a TU can be a function of the mutual inductance at the antenna.The mutual inductance is proportional to the flux times the antennawindings at the TU per current of the transmitting pill or other TU. Theflux through the TU antenna from the B field model and the antennamodels can be known. With the training dataset available, a linearregression can be performed to find the differential phase of the systemTUs from a pill. The flux through an TU for a pill at

with normal {circumflex over (N)}_(p) is given as:

$\begin{matrix}{{\Phi\left( {{\overset{\bot}{X}}_{P,i},{\hat{N}}_{p}} \right)} = {\int{\overset{\bot}{B}\bullet{\hat{N}}_{A}{d({Area})}}}} & (10)\end{matrix}$

Where the B field is given by the dipole model and {circumflex over(N)}_(A) is the TU unit normal. The Flux can be approximated as the areaA times the B-field at the center of the TU antenna. The mutualinductance between TU and pill is then found from the flux from a pillat a given location as

$\begin{matrix}{{M\left( {{\overset{r}{X}}_{P,i},{\hat{N}}_{p}} \right)} = \frac{N_{2}{\Phi\left( {{\overset{r}{X}}_{P},{\hat{N}}_{p}} \right)}}{I_{c}}} & (11)\end{matrix}$

Where N₂ is the number of turns in the TU, and I_(c) is the current inthe pill coil. The phase for a given TU was described by the complexcurrent by for a given pill and TU as

$\begin{matrix}{\phi_{pi} = {\tan^{- 1}\left( \frac{1 + K_{pi}^{2}}{{K_{pi}^{2}{R_{ai}/\omega}\; L_{a}} - {{R_{pi}/\omega}\; L_{p}}} \right)}} & (12)\end{matrix}$

Where L_(a) is the self-inductance of TU, L_(p) is the self inductanceof the pill, R_(ai) is the resistance of the coil in the TU, ω is theangular frequency of the pill, R_(pi) is the pill coil resistance andK_(Pi) is the coupling coefficient between pill and TU and is given as

$\begin{matrix}{K_{pi} = \frac{M\left( {{\overset{r}{X}}_{P},{\hat{N}}_{p}} \right)}{\sqrt{L_{a}L_{p}}}} & (13)\end{matrix}$

The pill self-inductance is about one □H and the TU self-inductance isabout tens of nH.

The phase difference, Δϕ_(i,j), between TU and TUj is found as thedifference of phases for current in TUi and TUj:

$\begin{matrix}{{{\Delta\phi_{i,j}} = {{\tan^{- 1}\left( \frac{1 + \left( \frac{M\left( \;{{\overset{r}{X}}_{P,i},{\hat{N}}_{p}} \right)}{\sqrt{L_{a}L_{p}}} \right)^{2}}{{\left( \frac{M\left( {{\overset{r}{X}}_{P,i},{\hat{N}}_{p}} \right)}{\sqrt{L_{a}L_{p}}} \right)^{2}{R_{ai}/\omega}L_{a}} - {{R_{pi}/\omega}L_{p}}} \right)} - {\tan^{- 1}\left( \frac{1 + \left( \frac{M\left( {{\overset{r}{X}}_{P,j},{\hat{N}}_{p}} \right)}{\sqrt{L_{a}L_{p}}} \right)^{2}}{{\left( \frac{M\left( {{\overset{r}{X}}_{P,i},{\hat{N}}_{p}} \right)}{\sqrt{L_{a}L_{p}}} \right)^{2}{R_{ai}/\omega}L_{a}} - {{R_{pi}/\omega}L_{p}}} \right)}}},} & (14)\end{matrix}$

Where the mutual inductance between pill and i and pill and j arecalculated in the model.

This modeled phase difference from the pill between TU_(i) and TU_(j)can be corrected by the second order coupling between all TUs. Thecorrection to the phase difference due to the interactions of all theantennas that are coupled by the coupling terms K_(i,j) and phase shiftsfrom coupling is found by solving the following equations for four TUs:

A ₁₂ e ^(iϕ) ¹² =K ₁₂ G ₂(ω)+K ₁₃ G ₃(ω)K ₃₂ G ₂(ω)+K ₁₄ G ₄(ω)K ₄₂ G₂(ω)

A ₁₃ e ^(iϕ) ¹³ =K ₁₃ G ₃(ω)+K ₁₄ G ₄(ω)K ₄₃ G ₃(ω)+K ₁₂ G ₂(ω)K ₂₃ G₃(ω)

A ₁₄ e ^(iϕ) ¹⁴ =K ₁₄ G ₄(ω)+K ₄₂ G ₂(ω)K ₂₁ G ₁(ω)+K ₁₃ G ₃(ω)K ₃₄ G₄(ω)

A ₂₃ e ^(iϕ) ¹² =K ₂₃ G ₃(ω)+K ₃₄ G ₄(ω)K ₄₂ G ₂(ω)+K ₂₁ G ₁(ω)K ₁₃ G₃(ω)

A ₂₄ e ^(iϕ) ²⁴ =K ₂₄ G ₄(ω)+K ₂₃ G ₃(ω)K ₃₄ G ₄(ω)+K ₂₁ G ₁(ω)K ₁₄ G₄(ω)

A ₃₄ e ^(iϕ) ³⁴ =K ₃₄ G ₄(ω)+K ₃₂ G ₂(ω)K ₂₄ G ₄(ω)+K ₃₁ G ₁(ω)K ₁₄ G₄(ω)   (15)

Where the G_(k)(ω) are functions of the phase shift for a given circuitdesign approximately found as having a circuit gain at the TU_(k) of4.69 and a phase of about 76.2 degrees. The A_(ij) are the measuredamplitudes when TU_(i) is transmitting to TUj. The φ_(i,j) are the phasedifferences from Transmit Unit TU_(i) transmitting to TU_(j). Theamplitudes are symmetrical and independent of which way the transmissionis going. The equations are non-linear and can be solved by iteration tofind the K_(ij)'s and the G_(k)(ω) where for four TUs, i=1,4, j=1,4,i≠j, and k=1,6. There are six independent amplitude measurements, andsix phase differences. There are six K_(ij) unknowns, and six phaseshifts and amplitude unknowns. For five TUs, the number of equationsgoes to ten and the unknowns become 20.

Once the phase shifts and coupling coefficients are known, the effect ofthe secondary coupling can be backed out of the phase measurementsleaving the phase shift from the pill interaction alone. The analysisdescribed above including the equations can be implemented in thecalculator module. This phase shift then if proportional to the timedelay of arrival of the waves from the pill to the TU. This informationcan then be used in the multilateration to find the pill location in 3D.

c. Second Order Coupling Correction—2

In one embodiment, the system is made up of n antennas (say five, i=1,5)and one pill (P). The current induced by the pill in TU_(i) consists ofpill induced current plus all the antenna currents that are induced fromthe pill in the other antennas and interacting with the TU_(i). This isto say to first order, the pill induces a current in the TUs. Everyother TU₁'s induced currents induces a current in every other TUi, wherei=1 to 5 and i≠j. This antenna TU_(j) interaction with antenna TU_(i) isa second order effect and should be small. However in fact, such secondorder effects may be important and can give an accurate phase andamplitude model. The analysis described here including the equations canbe implemented in the calculator module.

The total effective amplitude can be proportional to the total magneticflux, φ_(tot,i), through antenna TU_(i), from all effects up to secondorder. The total flux from the pill and the pill induced current inantennas j is given as

$\begin{matrix}{{A_{{tot},i}e^{i_{m}\phi_{{tot},i}}} = {{A_{Pi}e^{i_{m}\phi_{Pi}}} + {\sum\limits_{\underset{j \neq i}{j = 1}}^{n}{A_{ji}K_{ji}K_{{Pj}\;}A_{Pj}e^{i_{m}{({\phi_{pj} + \phi_{ji}})}}}}}} & (16)\end{matrix}$

The first product on the right hand side (rhs) is a first order effectfrom the pill; the second summation term is the amplitude and phase inantenna i from all other antennas j, a second order effect; theA_(Pi)e^(i) ^(m) ^(ϕ) ^(Pi) term is the phase of the induced currentfrom the pill in antenna i. The i_(m) in the exp function is theimaginary constant √{square root over (−1)}. The e^(i) ^(m) ^((ϕ) ^(pj)^(+ϕ) ^(ji) ⁾ is the phase shift induced on antenna i from the currentinduced in antenna j from the pill. In some embodiments, thedifferential phase of current in i from TU_(j) is nearly constant andfound from the SPICE model calculations to be approximately 76.2 degreesfrom the phase from the current induced from the pill in antenna j.There are third order effects from the induced currents in TUi's fromother TU's.

The K_(ij) values are those found from the antenna-to-antenna solutionsof equation (15) above. The amplitudes from the pill are found from thecalculation of the flux through the TU from the pill. The amplitudesfrom TUi to TUj are found from the flux from TUi to TUj. The amplitudefrom the pill in antenna i, A_(Pi), is proportional to the flux throughTU_(i) from the pill:

$\begin{matrix}{\Phi_{Pi} = {{\int{{{\overset{r}{B}\left( {{\overset{r}{X}}_{Pi},I_{c}} \right)} \cdot d}\;{\overset{r}{A}}_{i}}} = {N_{P}{B\left( {\overset{r}{X}}_{Pi} \right)}Area_{i}}}} & (17)\end{matrix}$

Where the rhs contains the average integral over the B field dotted intothe surface area normal; the cosine of the angle between the area normaland the B field is contained in B′. The number of turns in the pill,N_(P) is shown explicitly. The parameter ω is the angular frequency ofthe pill transmitter in radians/sec; the

vector contains the geometry information from the pill to the antenna iin pill centric coordinates with pill z_(P)-axis aligned along thedipole axis.

is the current magnitude of the vector loop current in the pill (andwill just be called I_(c) here) and for modeling purposes will be a freeparameter of the model. The variable

is the area of the antenna i is a vector quantity in the direction ofthe normal to the surface defined by the right hand rule to be

$\begin{matrix}{\overset{r}{n} = {\overset{r}{r} \times {\overset{\bot}{I}}_{c}}} & (18)\end{matrix}$

Where

is the position vector from pill to TU.

The phase difference is a function of the circuit layout of the TU andthe pill. SPICE Calculation program (Cadence Design Systems, Inc) can beused to find the correction phase to the phase calculated by the firstorder model. The SPICE calculations use the coupling coefficients todetermine the phase shift. The corrections in phase from the SPICEcalculations then can be used to correct the model. In otherembodiments, the calculator module can implement the analysis describedabove and automatically calculate the correction. Equations (16) can besolved in a non-linear process and give the Kg values and the phaseshifts and agree with th SPICE model.

XI. Training/Calibration

FIG. 8A illustrates an embodiment of a process 800 for calculatingsystem parameters. This process can be implemented by the system 100described herein. In particular, each of these processes can beimplemented by one or modules in the patient monitor 20 described above.

The calibration module can build an initial calibration or training setconsisting of phase and amplitude measurements of the pill at manyrandomly selected locations in a volume surrounded by the antennas. Weuse the calibration set in a multivariate linear regression analysis tofind the pill location. The calibration training set is measured withthe TUs on a frame that has a configuration of the rough location of theTUs, as they would be placed on the patient. This does not have to beaccurate since the antenna TU locations will be located with the TUs onthe patient. The calibration training set is to measure anomalous roomeffects and other pill distortions experimentally.

Referring specifically to FIG. 8A, at block 810, the calibration modulein the patient monitor can receive the location of TUs. The TU locationscan be calculated using techniques described below or can also beentered into the patient monitor 20 via an input (e.g. keyboard,display). At block 812, the calibration module can receive a firstlocation of the pill via an input or a previous calculation. The patientmonitor 20 can generate a trigger signal at block 814 for transmissionvia the stimulus antenna to the pill 14. In response to the triggersignal, the pill 14 can transmit a signal waveform that can be receivedby the plurality of TUs 16. At block 816, the monitor 20 can collect thereceived signals from the TUs. The measurement module can measure thephase and the amplitude of the collected signals at block 818. Thecalculator module can also calculate the phase differences between oneor more pair of the collected signals. The measurement set can be storedin the memory of the monitor 20. The calibration module can repeat thesteps from blocks 812 to 818 in response to the pill moving to adifferent location than the first location.

In an embodiment, the pill is moved at various locations in a latticecalibration structure as shown in FIG. 8B. The lattice calibrationstructure can include several towers 1520, 1522 for moving the pill 1514along the length of the towers. Several measurements can be taken fordifferent positions of the pill in the lattice to calculate systemparameters according to process 800.

In one embodiment, the initial training set can include phase andamplitude from say 12,000 points. This can be from 10 heights, 10X-axis, 10 Y-axis locations and 12 angles at each pill location. Thoughthis is a large amount of collected data, fifteen data words plusmetadata, the measuring and the processing can be done automatically andonly the 12,000×15 data words (˜720 kB) may need to be saved on thecomputer and used for analysis.

When measurements from all the pill locations are completed, thecalibration module, at block 822, can calculate system parameters fromthe stored measurement set of phase, amplitude shifts, and phasedifferences. Furthermore, second order effects may also be taken intoaccount during the calibration process. The collected dataset can beused to validate the model estimates of phase and amplitude of theapproximate volume of the patient as described above.

FIG. 9 illustrates a block diagram for calculating location estimate.For the plurality of TUs, the amplitude and phase can be measured from I& Q. The amplitude shifts (square root of I-squared summed withQ-squared) of the captured signals vary with the pill location. Theamplitude shift can also be a function of the mutual inductance. Tofirst order, they will be functions of the Z height of the pill for eachX and Y for the training set. The variation of the amplitude with Z canroughly be approximated as a quadratic. If each set of Z measurements ofamplitude at all X, Y, θ and φ in the training set can be taken as aseparate dataset. Each capable of returning estimated Z value of anunknown Z value of the pill. For discussion, call each set of Zmeasurements of amplitude a tower of training set data. There would be1200 towers of Z measurements. We can fit quadratics to each tower ofdata with ten Z points in the fit as a function of Z. For an unknownpill location or validation location, we then calculate the Z locationestimated from inverting the amplitude quadratic fit. This process canlead to at most two solutions of the pill Z height for a given tower.There are five amplitudes and thus as many as 10 different solutions.The correct solution is taken as the one with minimum variance for alltowers. This process leads to a Z height for a given tower, with X andY, θ and φ locations. If two or more variances are close to each other,the Z height for that solution is kept as a possible first guesssolution to be further analyzed. The above process can be made veryrapid if the coefficients of the amplitude fits of the training set arepre-computed and stored. The pill Z height location for a given towercan give the X, Y, Z, and Normal for a starting guess of the non-linearlocation process. This can be the starting guess for the non-linearprocessing which may need a guess within ten centimeters of the answerto assure that it converges to the correct answer.

XII. Physiological Monitor/Display

In some of the embodiments described above, the location of the pill istracked relative with respect to the location of the TUs. It may be morehelpful for a physician to see the location of the pill with respect tothe patient's anatomy. For example, it may be important for the doctorto see that the pill might be blocked in a portion of the smallintestine. Accordingly, the translator module implemented in the patientmonitor 20 can translate antenna-centric coordinates to body-centriccoordinates. The processes described above can be used to measure thelocations of the TUs an instant (e.g. 100 ms) before pill locationprocess. Subsequently, the pill can be located in the antenna-centriccoordinates using one of the methods described above. Subsequently, thetranslator module may use one or more transformation matrix stored inthe memory of the patient monitor to translate from antenna-centriccoordinate of the pill location to body centric. The transformationmatrices may correspond to different arrangements of TUs relative to thebody of the patient. An example TU arrangement is shown in FIG. 11A.Once the pill location is transformed to body centric coordinates, thetranslator module can send the processed data to the display 30.

FIG. 10 illustrates an embodiment of a display 30 included in thepatient monitor 20. The display 30 may show real time location of thepill 14 with respect to human anatomy. In another embodiment, thedisplay 30 may be updated periodically over time intervals.

XIII. Drug Delivery Pill

There are numerous disadvantages with orally administered medications.For instance, orally administered medicines may require higher dosagebecause their efficacy may diminish by the time they reach a targetlocation in the body. To accomplish a given dosage for a target tissueregion in the GI tract, the dosage of an orally administered medicationmay need to be sufficient for the entire body, or typically numerousbody systems, in order to achieve the prescribed dosage at the region ofinterest. Orally administered medication may also be harmful to parts ofthe patient's body that the medication is not targeted toward. Drugsthat are orally ingested may also be affected by stomach acid.

It is possible to administer medications in ways other than orally,including rectally or with more invasive procedures such ascatheterization. Some of the current drug delivery systems may not beable to reach remote sections of the GI tract without surgical intrusionsuch as a catheter or a similar inserted, invasive device. Yet suchprocedures may result in patient discomfort, tissue damage, and increasepotential for infection. In some patients, large dosage and/or anon-targeted dosage can result in adverse side effects in some medicaltreatment situations. For convenience, this specification refers to“medications” and “drugs” interchangeably.

As discussed above, the movement of the pill 14 can be tracked as ittraverses through the GI tract of the patient. In some embodiments, thepill 14 can be advantageously used for delivering a drug at a particularlocation in the patient's body based in part on tracking the movement ofthe pill 14. Targeted drug delivery may have higher effectiveness intreating some conditions, or may allow the use of some drugs that cannotbe administered systemically. Location-based dispensing of drug mayincrease therapeutic value and pharmacological efficacy of certaindrugs, such as insulin, chemotherapy, or others. In some embodiments,the pill 14 can release drugs in the region of interest or can targetlocations along the GI tract. The pill 14 can be also used inchemotherapy or targeted drug therapy.

FIG. 12 illustrates an embodiment of a system 1200 for transmitting atrigger signal to the pill 14 as it traverses through the body of thepatient. As discussed herein, in some embodiments, the pill 14 transmitsa signal to the receiver antennas 16, which are collected by the patientmonitoring system 20 to calculate, using hardware processors, thelocation and current transit time of the pill 14 in the GI tract. Thelocation may be in antenna-centric coordinates or transformed tobody-centric coordinates. The patient monitoring system 20 can displaythe location of the pill transmitter 14. The patient monitoring system20 can also send the location estimates over a network 1220 to one ormore user systems 1214.

The user system 1210 can include a display unit 1212 and a datainterface 1214. The user system 1210 can be a computing device,including a mobile computing device such as a laptop, a smartphone, anaugmented-reality wear, or a smart wearable device. The user system 1210can include a data interface 1214 to receive an input from a user and inparticular, a medical clinician. The data interface 1214 can include atouch screen or a keyboard of a computing device or any other electricalor mechanical interface. In some embodiments, the data interface 1214can include a push button. In some embodiments, the patient monitor 20includes the user system 1210. The input received by the data interface1214 can be transmitted over a wired or wireless connection to thepatient monitor 20.

In some embodiments, the input can be transmitted over the network 1220.The user systems 1210 can also remotely communicate with the patientmonitor 20 through the network 1220. The user systems 1210 can includethick or thin client software that can access the patient monitor system20 through the network 1220. The network 1220 may be a local areanetwork (LAN), a wide area network (WAN), such as the Internet,combinations of the same, or the like. For example, the network 1220 caninclude an organization's private intranet, the public Internet, or acombination of the same. In some embodiments, the user software on theuser system 1210 can be a browser software or other applicationsoftware. The user system 1210 can communicate with the patient monitor20 through the browser software. In certain embodiments, some of thepatient monitor 20's functionality can be implemented on the usersystems 1210. The network 1220 is optional in some embodiments, as theuser system 1212 can connect directly to the patient monitoring system20 (or a clinician can directly interact with the patient monitoringsystem 20 via input and/or output devices of the system 20).

Clinicians can activate a feature or a component of the pill 14 usingthe data interface 1214. For example, a clinician can review the displayunit 1212 and identify that the pill 14 swallowed by a patient is at aparticular location in the GI tract of the patient's body. An exampledisplay unit 1214 is shown with respect to FIG. 10. The clinician maydecide to dispense medication stored in a reservoir of the pill 14 atthis particular location. Accordingly, the clinician can enter his orher selection using the data interface 1214 to cause the pill 14 todispense medication from its reservoir. The patient monitoring system 20may receive the clinician's selection. Based on the selection, thepatient monitoring system 20 can generate a trigger signal for thestimulus antenna 18 to transmit to the pill 14. In some embodiments, thetrigger signal can include a message, such as coded message, based onthe received selection from the clinician. For instance, the pill 14 mayinclude more than one feature that can be activated based on the triggersignals. Coded messages can enable the pill 14 to activate the featurecorresponding to the clinician's selection. Messages can be coded usingASK or other modulation techniques. The pill 14 can decode the triggersignal received by the pill's receive circuit 216 and activate one ofits features.

As discussed herein, the pill 14 may include other features or sensors.For example, if the pill 14 has a camera, the clinician can request totake a picture using the data interface 1214. In some embodiments, thepill 14 can include a camera, an on-board laser, an electricalstimulating sensor, or a lab on a chip. A lab on a chip can includesensors for detection of analytes. The clinician can request that one ofthese features of the pill 14 be activated.

FIG. 13 illustrates an embodiment of a pill 14 that can be tracked as ittraverses through a patient's body using the systems and methodsdescribed above. In the illustrated embodiment, the pill 14 includes oneor more drug reservoirs 1302 for storing a single chemical entity or amixture of chemical entities that individually or collectivelyconstitute one or more medications. The chemical entities can include aliquid, gas, solid, or a mixture. The chemical entities may havetherapeutic properties. The size of the reservoir(s) 1302 can be afunction of the size of the pill and available space in the pill. Thereservoir(s) 1302 can be made of a glass, plastic, or other materialcapable of storing the drug. The amount of the chemical entity stored inthe reservoir may be a function of dosage or a function of size or afunction of both. The reservoir 1302 may also include inert chemicalentities together with the drugs or alone, for example, as a placebo. Insome embodiments, the reservoir 1302 can include multiple compartmentsfor storing the same or different chemical entities.

The pill 14 can dispense chemical entities from different compartmentsat the same or different locations along the GI tract based on thereceived trigger signal. For example, in some embodiments, the pill 14can include three compartments where each compartment includes adifferent chemical entity. The pill 14 can dispense a first portion of afirst chemical entity from the first compartment at a first location ata particular time based on the received trigger signal from the patientmonitor. In some embodiments, the pill 14 can dispense a portion of asecond chemical entity from the second compartment at the same locationat about the same time as dispensing the first chemical entity inresponse to the received trigger signal or a new trigger signal.Furthermore, the pill 14 can dispense the third chemical entity at adifferent location than the dispersal location of the first chemicalentity in response to another trigger signal. Accordingly, the pill 14can be configured to release medication from multiple compartments in anorder selected according to the trigger signal from the patient monitor.

The pill 14 can include a drug dispensing mechanism 1304 for releasingthe chemical entity(ies) stored in the reservoir 1302 to an environmentexternal to the pill 14. The dispensing mechanism 1304 can include avalve or an aperture, as a few non-limiting examples. Drugs can bedispensed using a pressure difference or by puncturing the reservoir1302. The drug dispensing mechanism 1304 may also include a miniaturesyringe with a piston to drive the drug from the reservoir through anorifice in the pill wall. In some embodiments, the dispensing mechanism1304 is a miniature pump that moves the drug from the reservoir 1302through any tubing to an exit orifice that opens in the pill wall. Thedosage can be controlled based on the trigger signal.

The pill 14 can also include a trigger circuit 1306 to activate afeature of the pill 14. For example, the trigger circuit 1306 caninclude circuitry to operate the drug dispensing mechanism. In someembodiments, the trigger circuit 1306 may include a hardware processoror can be implemented in a hardware processor as described herein. Thetrigger circuit 1308 can, for example, activate the drug dispensingmechanism 1304 described above. The trigger circuit 1308 can also beimplemented using analog circuitry, which may (but need not) betriggered by a separate hardware processor. The circuitry of the pill 14may therefore include a single hardware processor that controlsoperations of the pill 14, including drug delivery, or multipleprocessors used for different functions of the pill 14, including drugdelivery.

The pill 14 can include receive and transmit circuitry as describedherein. For example, signal generation circuitry 1314 in the pill 14 cangenerate a signal for transmission from the pill antenna 1308. Thetransmitted signal can be used to calculate location of the pill 14 asdiscussed above. Before transmission, the signals may be processed by anRF Amplifier and Antenna Select circuit 1310 to condition signals fortransmission. The pill 14 can also include a power supply or a battery1312 to power the onboard electronics.

In some embodiments, the pill 14 includes a control circuit 1316 tocontrol operations of the pill 14. The control circuit 1316 can includeelectronic circuit elements and/or a hardware processor. The controlcircuit 1316 can also be implemented in a hardware processor. Thecontrol circuit 1316 can process received signals such as the triggersignal to instruct one of the components of the pill 14. For example,the control circuit 1316 can determine that the trigger signalcorresponds to releasing drug or turning on the pill transmitter. Insome embodiment, the control circuit 1316 can demodulate coded triggersignals.

FIG. 14 illustrates an embodiment of a process 1400 for generating atrigger signal for transmission to the pill 14. This process can beimplemented by any of the systems described above. In particular, eachof these processes can be implemented by one or more modules in thepatient monitor 20 described above. As discussed above, receiverantennas 16 located near the body of the patient can receive atransmitted signal from the pill 14. At block 1402, the patient monitor20 can collect the received signals from the receiver antennas 16. Thepatient monitor 20 can then, at block 1404, calculate a location of thepill in either body-centric or antenna-centric coordinates using any ofthe techniques described above. In some embodiments, the patient monitor20 can store the coordinates of the pill 14 in its memory and can builda map of the GI tract as the pill traverses through the GI tract.

At block 1406, the patient monitor 20 can determine whether to generatea trigger signal for transmission to a pill 14. In an embodiment, thetrigger signal is transmitted by stimulus antenna 18. Trigger signalsmay be used by the patient monitor to activate a feature of a pill. Insome embodiments, the pill 14 transmits a waveform to the receiverantennas 16 for location determination in response to a trigger signal.As discussed above, trigger signals may be generated automatically bythe patient monitor 20 or in response to an input from external systemsor actions from clinicians.

In some embodiments, at block 1408, clinicians can supply an input (suchas a touchscreen press or button press) on the patient monitor 20 orsend a request via a user system 1214 to generate a trigger signal fromthe patient monitor 20. The user systems 1214 may also communicatedirectly with the pill 14 without using a patient monitor 20. Forexample, the user system 1214 may include an antenna to send a wirelesssignal to the pill 14 to activate a feature of the pill. In someembodiments, clinicians can track the pill 14 on a display and identifythat it is at a location of interest, such as the small intestine.Accordingly, the clinician can push a button or make a selection usingthe data interface 1214 to dispense medication or activate any otherfeature of the pill (additional examples of which are described below).The patient monitor 20 can receive the selection from the physician andgenerate a trigger signal for transmission to the pill 14 as illustratedin block 1410.

Clinicians may also be able to save parameters for generating triggersignals. For example, clinicians can determine that a trigger signalshould be generated at a particular time and/or location after the pillis swallowed by a patient. A clinician can select on a user system 1210to dispense medication when the pill enters a portion of the GI tract,such as the upper deodenum. The patient monitor 20 can track the pill 14in real time or periodically according to the spatial and temporalresolution established by the system in the patient's treatment regime.In some embodiments, the motility measurement may be tracked everysecond, or at faster or longer intervals, with spatial resolution of onecentimeter uncertainty in three dimensional space or better. Theclinician can also save dosage of the medication to be dispensed. Thepatient monitor 20 can store the preset parameters received from theclinician using the user system 1210.

The patient monitor can compare the current location of the pill 14 inthe GI tract with the preset parameters and determine that the pill isin the location selected by the clinician. In response to thedetermination, the patient monitor 20 can generate a trigger signal fortransmission to the pill 14 to dispense a particular dosage ofmedication at the desired location. In some embodiments, the pill 14 maybe triggered by the clinician or automatically at several locationsalong the GI tracts and at different times. For example, a physician mayprescribe a single release at a given location, or a timed release withslower dispensing, or coordinate dispensing with other clinicalactivities or patient conditions, over a period of time. The patientmonitor 20 can generate trigger signals according to the physician'sinstructions or automatically based on the physician's prescription.

In some embodiments, the pill 14 can automatically dispense medicationat a location of interest without receiving an input from the clinician.For example, the patient monitor 20 can determine that the pill 14 isexperiencing a particular motion or speed and identify the locationbased on the detected motion. In some sections of the GI tract, the pill14 can move back and forth because of the muscle contractions or fluiddynamics, while in other GI tract sections, the pill 14 may experiencehigh turbulence or rotation. Accordingly, the patient monitor 20 candetermine that the pill 14 is at a particular location based on themotion experienced by the pill 14. Based on the determination, thepatient monitor 20 can generate a trigger signal to activate a featureof the pill. For instance, the patient monitor 20 can determine that thepill has left the stomach and generate a trigger signal to dispensemedication so that the stomach acid does not deteriorate the therapeuticeffectiveness of the medication. In an embodiment, the patient monitor20 can determine that the pill has left the stomach based on continuoustracking of the pill. For example, this determination can be based onthe shape of the duodenum, connecting the stomach pylorus to thebeginning of the small intestine. The patient monitor can identify theshape based on the motion and orientation of the pill. Based on thisdetermination, the patient monitor 20 can generate a trigger signal tosend to the pill, which can then initiate the release and dispensemedication to the region of clinical interest. In some embodiments, thedetermination can be based on an amount of time that the pill 14 hasbeen in the GI tract after it was swallowed by the patient.

As discussed above, the pill can activate one of its components orfeatures in response to receiving a trigger signal. While theembodiments discussed above were described with respect to dispensingmedication, other functionalities of the pill 14 can also be triggered.For example, in some embodiments, the pill 14 may include one or moreon-board LEDs, surgical blades, or lasers. The pill 14 may also includea lab-on-a-chip. Thus, the trigger signal can be used to activate afeature of a pill at a particular location.

The embodiments of pill described above relate to operating in a medicalenvironment. However, the systems and methods described above withrespect to the pill transmitter 14 and the patient monitoring system canalso be used in an industrial environment. In one embodiment, the pillor a container including a transmitter can be used to release anymaterial in an industrial manufacturing location where the location ofthe container can be identified in a three dimensional space by amonitor. Accordingly, the transmitter and receiver antenna systems canbe used with respect to a unit being manufactured, assembled, orintegrated on a production line. This could include the application ofadhesives, paint, protective coatings, or other materials by a robotic,or a hydraulic system, or other source mechanism. For example, therobotic arm can include a transmitter and the location can be trackedfor activating a feature at a particular location as discussed herein.In some instances, there may be multiple transmitters, for example, oneon the robotic arm and another one on the item to be assembled so thelocation of both the arm and the item can be tracked. Further, thetransmitter and receiver systems described above can be used formonitoring or fault detection or in the manufacturing of precisionproducts.

XIV. Appendix A—Mutual Inductance Mutual Inductance of Two Coils

Referring to FIG. 11B, there are two coils, called a “primary” (thepill, or “tag”) and a “secondary” (the receiving antenna, TU), floatingin space:

The center of the antenna is at r relative to the pill, at coordinates(x, y, z), which we assume are known. The antenna has area A directed inwhat the FIG. 11B calls the z′ direction, or the vector A=

. The pill creates a magnetic field B(x,y,z) at the antenna, which hasonly cylindrical radial (φ and z components relative to the pill.

We want the flux of the field that passes through the antenna, which isΦ=∫B·dS taken over a surface S whose boundary is the antenna perimeter.We can write Φ=BavA, where Bay is the surface average value of B.

If r is larger than either coil diameter, then Bay can be taken to bethe component of B(x,y,z) in the z′ direction, evaluated at the antennacenter. Bρ and Bz are given below. So to evaluate the flux

Φ=A·B(r)=A·(

+B _(ρ){circumflex over (ρ)})=A(

·

+

·{circumflex over (ρ)}B _(ρ))  A(1)

we will need the z and ρ components of

,

·

and

·{circumflex over (ρ)}. They are obtained as follows.

Needed Components of Antenna Area

We know the direction

of the pill magnetic moment, and the direction

of the antenna area. Both are known in a single coordinate system, so itis easy to evaluate

·

≡cos χ  A(2)

where χ is the angle between

and

. cos χ is the component of

parallel to

.

The other needed component is that of

parallel to ρ. Using ρ=x{circumflex over (x)}+yŷ=r−

we have

$\begin{matrix}\begin{matrix}{{{\hat{z}}^{\prime} \cdot \hat{\rho}} = {\frac{1}{\rho}{{\hat{z}}^{\prime} \cdot \rho}}} \\{= {\frac{1}{\rho}{{\hat{z}}^{\prime} \cdot \left( {{x\hat{x}} + {y\hat{y}}} \right)}}} \\{= {\frac{1}{\rho}{{\hat{z}}^{\prime} \cdot \left( {r - {z\hat{z}}} \right)}}} \\{= {\frac{1}{\rho}\left( {{{\hat{z}}^{\prime} \cdot r} - {z\;\cos\;\chi}} \right)}}\end{matrix} & {A(3)}\end{matrix}$

Again, either

·{circumflex over (x)} or

·y or

·r is readily evaluated using the known components of both vectors,which can be in pill centric locations. Here, of course, ρ=|ρ|=√(x2+y2).

The Mutual Inductance

Three field lines created by the pill are shown in the FIG. 11B. Thosefield lines pass through coil 2 inducing a voltage there across the endsof its coil. This voltage V2 is proportional to the rate of change ofthe flux through 2, and so to the rate of change of current I1 in coil1: V2=Mdl1/dt.

We seek the mutual inductance M, as a function of the relative positionof the two coils and their relative orientation. We will need relations(2) and (3)

Field of Coil 1—the Pill

Referring to FIG. 11C, A coil with current I has a magnetic moment m,directed along the loop axis (right hand rule). Its static magneticfield is azimuthally symmetric about m, and so has no azimuthalcomponent. At any point r=r{circumflex over (r)}, B is [Ja75, Eq (5.56),converted to SI]

$\begin{matrix}{{B(r)} = {\frac{\mu_{o}}{4\pi}\frac{{3\left( {\hat{r} \cdot m} \right)\hat{r}} - m}{r^{3}}}} & {A(4)}\end{matrix}$

This formula and the ones below are for a point dipole, or for r>>coildimensions.

r points to an observer at a general point,P(r)=P(x,y,z)=P(r,θ,φ)=P(ρ,z,φ) (for example, at the center of anothercoil). As before, ρ is the cylindrical radius from the z axis to P. Withm□z, {circumflex over (r)}·m=m cos θ, and {circumflex over (θ)}·m=−m sinθ, so the spherical components Br and Bθ of B are:

$\begin{matrix}{{B_{r} = {{\hat{r} \cdot B} = {{\frac{\mu_{o}}{4\pi}\frac{2{\hat{r} \cdot m}}{r^{3}}} = {\frac{\mu_{o}}{4\pi}2\cos\theta\frac{m}{r^{3}}}}}}{B_{\theta} = {{\hat{\theta} \cdot B} = {{\frac{\mu_{o}}{4\pi}\frac{{3\left( {\hat{r} \cdot m} \right)\left( {\hat{\theta} \cdot \hat{r}} \right)} - {\hat{\theta} \cdot m}}{r^{3}}} = {{+ \frac{\mu_{o}}{4\pi}}\sin\;\theta\frac{m}{r^{3}}}}}}} & {A(5)}\end{matrix}$

The cylindrical components Bρ and Bz of B are:

$\begin{matrix}{{B_{\rho} = {{\hat{\rho} \cdot B} = {{\frac{\mu_{o}}{4\pi}\frac{{3\left( {\hat{r} \cdot m} \right){\hat{\rho} \cdot \hat{r}}} - {\hat{\rho} \cdot m}}{r^{3}}} = {\frac{\mu_{o}}{4\pi}3\cos\theta\sin\theta\frac{m}{r^{3}}}}}}{B_{z} = {{\hat{z} \cdot B} = {{\frac{\mu_{0}}{4\pi}\frac{{3\left( {\hat{r} \cdot m} \right)\left( {\hat{z} \cdot \hat{r}} \right)} - {\hat{z} \cdot m}}{r^{3}}} = {\frac{\mu_{o}}{4\pi}\left( {{3\cos^{2}\theta} - 1} \right)\frac{m}{r^{3}}}}}}} & {A(6)}\end{matrix}$

The Cartesian components are:

$\begin{matrix}{{B_{x} = {{\hat{x} \cdot B} = {{\frac{\mu_{o}}{4\pi}\frac{{3\left( {\hat{r} \cdot m} \right){\hat{x} \cdot \hat{r}}} - {\hat{x} \cdot m}}{r^{3}}} = {\frac{\mu_{o}}{4\pi}3\cos\;{\theta sin\theta cos\varphi}\frac{m}{r^{3}}}}}}{B_{y} = {{\hat{y} \cdot B} = {{\frac{\mu_{o}}{4\pi}\frac{{3\left( {\hat{r} \cdot m} \right){\hat{y} \cdot \hat{r}}} - {\hat{y} \cdot m}}{4\pi r^{3}}} = {\frac{\mu_{o}}{4\pi}3\cos\;{\theta sin\theta sin\varphi}\frac{m}{r^{3}}}}}}} & {A(7)}\end{matrix}$

where azimuth angle φ is measured in the right-hand sense about z fromthe x axis toward the y axis (direction of I in the above sketch). Bz isthe same as in (6).

As stated, B_(φ)=0. The magnitude of B is

$\begin{matrix}{B = {\frac{\mu_{o}}{4\pi}\sqrt{1 + {3\cos^{2}\theta}}\frac{m}{r^{3}}}} & {A(8)}\end{matrix}$

These components are expressed in terms of the convenient sphericalcoordinates r, θ, φ relative to the x, y, z system of primary coil 1. Touse Cartesian coordinates, recall

r=√{square root over (x ² +y ² +z ²)}

ρ=√{square root over (x ² +y ²)}=r sin θ

x=ρ cos φ=r sin θ cos φ

y=ρ sin φ=r sin θ sin φ

=r cos θ  A(9)

At r>>loop radius, on the z axis all components are zero exceptBr=Bz=(μo/4π)2m/r3, and on the equator all components are zero exceptBθ=−Bz=(μo/4π)m/r3.

At any point, the unit vector b=B/B in the direction of the field is,from (4) and (8),

$\begin{matrix}{{b(r)} = \frac{{3\cos\theta\hat{r}} - \hat{z}}{\sqrt{{3\cos^{2}\theta} + 1}}} & {A(10)}\end{matrix}$

where

{circumflex over (r)}={circumflex over (x)} sin θ cos φ+ŷ sin θ sin φ+

cos θ  A(11)

Flux of Coil 1 Through Coil 2

As stated, the flux is approximately

Φ=A

·B(r)  A(12)

and is given in Eq (1), where

·

and

·{circumflex over (ρ)} are in Eqs (2) and (3).

Models of Coils

Let coil 1 have N1 turns of wire carrying current I1. Its area is A1, soits magnetic moment is

m ₁ =N ₁ A ₁ I ₁

  A(13)

Then its magnetic field is given by Eq(4) and the later expression forits components, with m replaced by m1. If there is a ferrite core ofrelative permeability μr1 (dimensionless), then (13) is replaced by

m ₁ =K ₁μ_(r1) N ₁ A ₁ I ₁

  A(14)

where K1 is a correction factor accounting for the aspect ratio of theferrite core (length/diameter) and the fraction of the core lengthoccupied by the wire turns. Similarly, let coil 2 have area A2, and N2turns. The emf generated in coil 2 by Φ is

$\begin{matrix}{{e\;{mf}_{2}} = {{N_{2}\frac{d\Phi}{dt}} = {M\frac{dI_{1}}{dt}}}} & {A(15)}\end{matrix}$

by definition of M.

Inserting the components of B from (6) with m1 from (14), Φ from (12) or(1) is

$\begin{matrix}{\Phi = {\frac{\mu_{o}}{4\pi}K_{1}\mu_{r1}N_{1}A_{1}I_{1}K_{2}\mu_{r2}A_{2}\frac{{3\cos\theta\sin\theta{{\hat{z}}^{\prime} \cdot \hat{\rho}}} + {\left( {{3\cos^{2}\theta} - 1} \right){{\hat{z}}^{\prime} \cdot \hat{z}}}}{r^{3}}}} & {A(16)}\end{matrix}$

Here we have allowed for coil 2 to have a ferrite core with parametersμr2 and K2, which would increase the flux through 2. And a ferrite corein coil 1 increases B and Φ at coil 2. r is the distance from the centerof coil 1 to the center of coil 2. θ is the polar angle to the center ofcoil 2 with respect to the z axis of coil 1, as in the above sketches.

Mutual Inductance

According to (15) M is N2 times the coefficient of I1 in Φ:

$\begin{matrix}{M = {\frac{\mu_{o}}{4\pi}K_{1}\mu_{r1}N_{1}A_{1}K_{2}\mu_{r2}N_{2}A_{2}\frac{{3\cos\theta\sin\theta{{\hat{z}}^{\prime} \cdot \hat{\rho}}} + {\left( {{3\cos^{2}\theta} - 1} \right){{\hat{z}}^{\prime} \cdot \hat{z}}}}{r^{3}}}} & (17)\end{matrix}$

M is in Henrys.

XV. Appendix B—Phase and Amplitude Measurements

This subsection describes a methodology for determining average phaseand average amplitude of a sampled waveform composed of many cycles of asinusoidal wave. The waveform consists of an RF pulse with a singleknown frequency, ω, and period T, which is sampled at every Δt secondsfor N samples. The amplitude and phase of the measured waveform at agiven transceiver location are a function of orientation and range tothe target; modulation of these two parameters due to motion will beslow compared to the carrier frequency. The technique described herewill track this slowly varying phase and amplitude over a large numberof carrier cycles to minimize error in the presence random noise.

In one embodiment, the signal is measured by sampling or real-timemeasurement of the in-phase (I) and the Quadrature (Q) signals bysampling the waveform. The near real-time Phase is measured at each TU.The phase is the arc tangent of the Q/I signal average over about onemillisecond of transmitted ASK waveform. The average amplitude is justthe square root of the I-squared and Q-squared signals. The extractionof the I and Q signals from the waveform is done using standard signalprocessing approaches. The extraction of the I and Q signals can beperformed in analog hardware in real time and averaged over time withthe average values of I and Q becoming more defined over time. When thesignal to noise reaches a given threshold, the signal I and Q are thenfurther analyzed to determine the location of the pill. The noise ismeasured an instant before the TU/TU transmits.

Well established frequency tracking techniques can used to extract areliable frequency estimate from all receive coils, allowing use of lowpower and low cost transmit coils with relaxed frequency tolerance. Forthe intended application, motion of the transmit coil will be slow andvariation in amplitude and phase due to motion will be several orders ofmagnitude lower in frequency than the carrier oscillator. Amplitude andphase due to the desired signal can be treated as essentially constantover thousands of carrier cycles. Given a known carrier frequency ω, thesignal is multiplied by sin(ωt) and cosine(ωt) to demodulate the signalinto I and Q components. These I and Q components determine bothmagnitude and phase of the signal measured at each transceiver coil.Multiplication of two sine waves generates sum and differencefrequencies; since the demodulation process uses the carrier frequency ωthe difference frequency will be 0 and the sum frequency will be 2ω. Ifthe measurement period exactly covers an integer number of carrier 2ωcycles then (neglecting noise) the sine and cosine demodulation processwill return exact values for I and Q. For general case, the AD samplingfrequency will not be an integer multiple of the carrier frequency, andan exact integer number of cycles in the measurement period will not beobtained. However the residual 2ω ripple is greatly attenuated by simplelow pass filtering as shown below.

Sin and Cosine Demodulation Details:

Given a transmitted sinusoidal waveform f(t) with angular frequency ωand phase ϕ, sampled at discrete times t_(i), the signal component dueto f(t_(i)) is given by:

f(t _(i))=

A _(j)

sin(ωt _(i)+ϕ)  B(1)

Where

A

is the mean of the slowly varying amplitude of the waveform over ameasurement period T_(j). The waveform at a given transceiver witharbitrary phase φ (with respect to the transceiver time base) can bedecomposed into sin and cosine phases

f(t _(i))=

A _(j)

[cos(ϕ)sin(ωt _(i))+sin(ϕ)cos(ωt _(i))]  B(2)

To extract the in-phase or cos(ϕ) component of the signal we multiplyequation (2) by sin(ωt_(i)). The new result is

f(t _(i))sin(ωt _(i))=

A _(j)

[cos(ϕ)sin(ωt _(i))sin(ωt _(i))+sin(ϕ)sin(ωt _(i))cos(ωt _(i))]   B(3),

which can be expanded to the form:

f(t _(i))sin(ωt _(i))=

A _(j)

[cos(ϕ)sin²(ωt _(i))+sin(ϕ)cos(ωt _(i))sin(ωt _(i))]  B(4),

Using the identities sin²(ωt)=½−½ cos(ωt) and sin(ωt)cos(ωt)=½ sin(2ωt),the above can be reduced to

$\begin{matrix}{{{f\left( t_{i} \right)}{\sin\left( {\omega t}_{i} \right)}} = {\left\langle A_{j} \right\rangle\left\lbrack {{{\cos(\phi)}\frac{1}{2}\left( {1 - {\cos\left( {2{\omega t}_{i}} \right)}} \right)} + {{\sin(\phi)}\frac{1}{2}{\sin\left( {2{\omega t}_{i}} \right)}}} \right\rbrack}} & {B(5)}\end{matrix}$

We can now average f(t_(i))sin(ωt_(i)) over all N samples in measurementperiod T.

$\begin{matrix}{{\frac{1}{N}{\sum\limits_{t}^{N}{{f\left( t_{i} \right)}{\sin\left( {\omega\; t_{i}} \right)}}}} = {\left\langle A_{j} \right\rangle{\frac{1}{N}\left\lbrack {{{\cos(\phi)}{\sum\limits_{i}^{N}\left( {\frac{1}{2} - {\frac{1}{2}{\cos\left( {2\omega\; t_{i}} \right)}}} \right)}} + {{\sin(\phi)}{\sum\limits_{i}^{N}{\frac{1}{2}{\sin\left( {2\omega\; t_{i}} \right)}}}}} \right\rbrack}}} & {B(6)}\end{matrix}$

The average value of the −cos(2ωt_(i)) and the sin(2ωt_(i)) discretetime samples over an integer number of carrier cycles is zero. Fornon-integer measurement periods, the averages

$\frac{1}{N}{\sum\limits_{i}^{N}{{- \frac{1}{2}}{\cos\left( {2\omega\; t_{i}} \right)}\mspace{14mu}{and}\mspace{14mu}\frac{1}{N}{\sum\limits_{i}^{N}{\frac{1}{2}{\sin\left( {2\omega\; t_{i}} \right)}}}}}$

are bounded and oscillatory with magnitude decaying as N increases whilethe average

$\frac{1}{N}{\sum\limits_{i}^{N}\frac{1}{2}}$

is independent of N.For large N covering many carrier cycles, the average value off(t_(i))sin(ωt_(i)) for measurement period j asymptotically approaches

$\begin{matrix}{\left\langle {{f\left( t_{i} \right)}{\sin\left( {\omega t}_{i} \right)}} \right\rangle = {{\frac{1}{N}{\sum\limits_{i = 1}^{N}{{f\left( t_{i} \right)}{\sin\left( {\omega t}_{i} \right)}}}} = {\frac{1}{2}{\cos(\phi)}\left\langle A_{j} \right\rangle}}} & {B(7)}\end{matrix}$

The average

f(t_(i))sin(ωt_(i))

in equation 5 determines the in-phase component of the waveform, I,averaged over the collected waveform. Dividing out the factor of ½,

I _(j)=2

f(t _(i))sin(ωt _(i))

=

A _(j)

cos(ϕ)  B(8)

Similarly, the quadrature phase component of the signal is may beobtained by multiplying f(t_(i)) by cos(ωt_(i)) and taking the averageover all cycles of the data set which gives

$\begin{matrix}{\left\langle {{f\left( t_{i} \right)}{\cos\left( {\omega t}_{i} \right)}} \right\rangle = {\left\langle A_{j} \right\rangle\left\lbrack {{\frac{\sin(\phi)}{N}{\sum\limits_{i}{\cos^{2}\left( {\omega t}_{i} \right)}}} + {\frac{\cos(\phi)}{N}{\sum\limits_{i}\frac{\sin\left( {2{\omega t}_{i}} \right)}{2}}}} \right\rbrack}} & {B(9)}\end{matrix}$

Which can be expressed as

$\begin{matrix}{\left\langle {{f\left( t_{i} \right)}{\cos\left( {\omega t}_{i} \right)}} \right\rangle = {\left\langle A_{j} \right\rangle\left\lbrack {{\frac{\sin(\phi)}{N}{\sum\limits_{i}\left( {\frac{1}{2} + {\frac{1}{2}{\cos\left( {2{\omega t}_{i}} \right)}}} \right)}} + {\frac{\cos(\phi)}{N}{\sum\limits_{i}\frac{\sin\left( {2{\omega t}_{i}} \right)}{2}}}} \right\rbrack}} & {B(10)}\end{matrix}$

which for large N reduces to

$\begin{matrix}{\left\langle {{f\left( t_{i} \right)}{\cos\left( {\omega t}_{i} \right)}} \right\rangle = {\left\langle A_{j} \right\rangle\left\lbrack \frac{\sin(\phi)}{2} \right\rbrack}} & {B(11)}\end{matrix}$

Dividing out the factor of ½,

Q _(j)=2

f(t _(i))cos(ωt _(i))

=

A _(j)

sin(ϕ)  B(12)

The demodulated values I_(j) and Q_(j) can now be used to determineamplitude A_(j) and φ of the slowly modulated waveform over measurementinterval Tj

A _(j)

=√{square root over (I _(j) ² +Q _(j) ²)}  B(13)

The phase of the waveform then is given as

$\begin{matrix}{\phi = {{\tan^{- 1}\left\lbrack \frac{Q_{j}}{I_{j}} \right\rbrack} = {\tan^{- 1}\left\lbrack \frac{\sin(\phi)}{\cos(\phi)} \right\rbrack}}} & {B(14)}\end{matrix}$

XVI. Additional Embodiments

In certain embodiments, trilateration (which uses distances or absolutemeasurements of time of flight from three or more sites) ortriangulation (which uses the measurements of absolute angles) methodsmay also be used to calculate one of the pill or TU locations, inconjunction with the multilateration or coupling methods. For example,trilateration or triangulation may be used as an estimate to feed in oneof the analysis described herein.

Placement of the antennas described herein can be on certain hard pointsof the body, such as areas of the skin abutting bone, so as to reducemovement and variability of placement of the antennas. Doctors may findit convenient, for instance, to be instructed to place the antennas onthe same hard spots for each patient, enabling repeatability and ease ofremembering how to place the antennas. However, this is only anembodiment, and the antennas can be place on other hard areas or softareas as well, or both soft and hard areas. Soft areas can include areasof the skin that do not directly abut the bone, such as areas over theabdomen, pectoral muscle (in some patients), shoulders (in somepatients), and the like. Further, hard spots may be softer in some obesepatients. Compensation factors can also be used to calculate pillposition based on the size of the patient, for example, by factoring inheight, weight, body mass index (BMI), or other patient measurements.

Further, the pill may be measured in fewer than 3 dimensions (e.g., 2dimensions) by using fewer antennas. For instance, the antenna on thepatient's back may be omitted while still providing 2D measurementcapability. 2D measurement capability can still be useful for motilitymeasurement and may be cheaper, easier, and faster to perform than 3Dmeasurements. Further, 2D measurements may be performed (e.g., without aback antenna) conveniently when it is desirable not to move a patient toplace the back antenna. Some patients with certain conditions or in theICU may be unwise to move for placing the back antenna, for instance. 2Dmeasurements may also be performed and output at the same time as 3Dmeasurements on the same display using a full set of 3D antennas.

Similarly, while the antennas may be adhered to the skin, in otherembodiments, the antennas can be positioned in a blanket, sheet, orarticle of clothing (such as a shirt, vest, or apron) that is draped atleast partially over a patient. Using such an arrangement can also bebeneficial for patients who may benefit from not moving to attach a backantenna, and for other patients. In still another embodiment, an antennacan be embedded in a bed sheet upon which the patient is placed, insteadof adhered to the patient's back or posterior part of the body. Thus, inan embodiment, the sheet may include an antenna, the patient may have anapron, sheet, or other article of clothing draped on the patient, oradhesive antennas, or any combination of the same.

The output provided by the system on a display can be a 2D or 3D outputshowing the position of the pill with respect to the patient's body (ora model thereof). In another embodiment, the output made by the systemcan also include a message regarding a characteristic of motility or ofthe GI tract encountered by the pill. For instance, the pill can outputto the display (or audibly) an indication that an obstruction has beendetected. This type of indication can be used in conjunction with or inplace of an image of the location of the pill.

XVII. Terminology

Embodiments have been described in connection with the accompanyingdrawings. However, it should be understood that the figures are notdrawn to scale. Distances, angles, etc. are merely illustrative and donot necessarily bear an exact relationship to actual dimensions andlayout of the devices illustrated.

Many other variations than those described herein will be apparent fromthis disclosure. For example, depending on the embodiment, certain acts,events, or functions of any of the algorithms described herein can beperformed in a different sequence, can be added, merged, or left outaltogether (e.g., not all described acts or events are necessary for thepractice of the algorithms). Moreover, in certain embodiments, acts orevents can be performed concurrently, e.g., through multi-threadedprocessing, interrupt processing, or multiple processors or processorcores or on other parallel architectures, rather than sequentially. Inaddition, different tasks or processes can be performed by differentmachines and/or computing systems that can function together.

The various illustrative logical blocks, modules, and algorithm stepsdescribed in connection with the embodiments disclosed herein can beimplemented as electronic hardware, computer software, or combinationsof both. To clearly illustrate this interchangeability of hardware andsoftware, various illustrative components, blocks, modules, and stepshave been described above generally in terms of their functionality.Whether such functionality is implemented as hardware or softwaredepends upon the particular application and design constraints imposedon the overall system. The described functionality can be implemented invarying ways for each particular application, but such implementationdecisions should not be interpreted as causing a departure from thescope of the disclosure.

The various illustrative logical blocks and modules described inconnection with the embodiments disclosed herein can be implemented orperformed by a machine, such as a general purpose processor, a digitalsignal processor (DSP), an application specific integrated circuit(ASIC), a field programmable gate array (FPGA) or other programmablelogic device, discrete gate or transistor logic, discrete hardwarecomponents, or any combination thereof designed to perform the functionsdescribed herein. A general purpose processor can be a microprocessor,but in the alternative, the processor can be a controller,microcontroller, or state machine, combinations of the same, or thelike. A processor can include electrical circuitry configured to processcomputer-executable instructions. In another embodiment, a processorincludes an FPGA or other programmable device that performs logicoperations without processing computer-executable instructions. Aprocessor can also be implemented as a combination of computing devices,e.g., a combination of a DSP and a microprocessor, a plurality ofmicroprocessors, one or more microprocessors in conjunction with a DSPcore, or any other such configuration. Although described hereinprimarily with respect to digital technology, a processor may alsoinclude primarily analog components. For example, some or all of thesignal processing algorithms described herein may be implemented inanalog circuitry or mixed analog and digital circuitry. A computingenvironment can include any type of computer system, including, but notlimited to, a computer system based on a microprocessor, a mainframecomputer, a digital signal processor, a portable computing device, adevice controller, or a computational engine within an appliance, toname a few.

The steps of a method, process, or algorithm described in connectionwith the embodiments disclosed herein can be embodied directly inhardware, in a software module stored in one or more memory devices andexecuted by one or more processors, or in a combination of the two. Asoftware module can reside in RAM memory, flash memory, ROM memory,EPROM memory, EEPROM memory, registers, hard disk, a removable disk, aCD-ROM, or any other form of non-transitory computer-readable storagemedium, media, or physical computer storage known in the art. An examplestorage medium can be coupled to the processor such that the processorcan read information from, and write information to, the storage medium.In the alternative, the storage medium can be integral to the processor.The storage medium can be volatile or nonvolatile. The processor and thestorage medium can reside in an ASIC. The ASIC can reside in a userterminal. In the alternative, the processor and the storage medium canreside as discrete components in a user terminal.

Conditional language used herein, such as, among others, “can,” “might,”“may,” “e.g.,” and the like, unless specifically stated otherwise, orotherwise understood within the context as used, is generally intendedto convey that certain embodiments include, while other embodiments donot include, certain features, elements and/or states. Thus, suchconditional language is not generally intended to imply that features,elements and/or states are in any way required for one or moreembodiments or that one or more embodiments necessarily include logicfor deciding, with or without author input or prompting, whether thesefeatures, elements and/or states are included or are to be performed inany particular embodiment. The terms “comprising,” “including,”“having,” and the like are synonymous and are used inclusively, in anopen-ended fashion, and do not exclude additional elements, features,acts, operations, and so forth. Also, the term “or” is used in itsinclusive sense (and not in its exclusive sense) so that when used, forexample, to connect a list of elements, the term “or” means one, some,or all of the elements in the list. Further, the term “each,” as usedherein, in addition to having its ordinary meaning, can mean any subsetof a set of elements to which the term “each” is applied.

While the above detailed description has shown, described, and pointedout novel features as applied to various embodiments, it will beunderstood that various omissions, substitutions, and changes in theform and details of the devices or algorithms illustrated can be madewithout departing from the spirit of the disclosure. As will berecognized, certain embodiments of the inventions described herein canbe embodied within a form that does not provide all of the features andbenefits set forth herein, as some features can be used or practicedseparately from others.

For purposes of summarizing the disclosure, certain aspects, advantagesand novel features have been described herein. It is to be understoodthat not necessarily all such advantages can be achieved in accordancewith any particular embodiment disclosed herein. Thus, the embodimentsdisclosed herein can be embodied or carried out in a manner thatachieves or optimizes one advantage or group of advantages as taught orsuggested herein without necessarily achieving others.

In certain embodiments, a method of locating and triggering apatient-swallowed pill transmitter can include receiving signals from aplurality of antennas disposed about a body of a patient, the signalsresponsive to a transmitted signal from a pill transmitter swallowed bythe patient. The method can also include identifying phase differencesof the received signals based at least partly on mutual inductancebetween the pill transmitter and at least some of the plurality ofantennas. Further, the method can include determining an initialestimate of a location of the pill transmitter within the body of thepatient based at least in part on the phase differences of the receivedsignals. In some embodiments, the method can include comparing saidlocation of the pill transmitter with a first target location. Themethod can also include sending a trigger signal to the pill transmitterbased on the said comparison, the trigger signal configured to cause thepill to deliver a medication responsive to receiving the trigger signal.In some embodiments, at least said estimating relative locations of theantennas is performed by processing electronics.

In certain embodiments, a system for locating and triggering apatient-swallowed pill transmitter can include processing electronicsthat can receive signals from a plurality of antennas disposed about abody of a patient, the signals responsive to a transmitted signal from apill transmitter swallowed by the patient. The processing electronicscan identify one or both of phase differences and amplitude shiftsassociated with the received signals. The processing electronics canalso estimate a location of the pill transmitter within the body of thepatient based at least in part on one or both of the phase differencesand the amplitude shifts of the received signals. Moreover, theprocessing electronics can transmit a trigger signal to the pilltransmitter, said trigger signal configured to activate a component ofthe pill transmitter. The system can also include a memory device thatcan store the location of the pill transmitter. Moreover, the system caninclude a display that can output the estimated location of the pilltransmitter.

In certain embodiments, a system for locating and triggering apatient-swallowed pill transmitter can include processing electronicsthat can receive signals from a plurality of antennas disposed about abody of a patient, the signals responsive to a transmitted signal from apill transmitter swallowed by the patient. The processing electronicscan identify one or both of phase differences and amplitude shiftsassociated with the received signals. The processing electronics canalso estimate a location of the pill transmitter within the body of thepatient based at least in part on one or both of the phase differencesand the amplitude shifts of the received signals. Moreover, theprocessing electronics can transmit an indication of the location of thepill transmitter to a user system. In addition the processingelectronics can receive an input from the user system corresponding toactivating a feature of the pill. The processing electronics can alsotransmit a trigger signal to the pill transmitter based in part on thereceived input. The system can include a memory device that can storethe location of the pill transmitter. Moreover, the system can include adisplay that can output the estimated location of the pill transmitter

1.-20. (canceled)
 21. A method of locating and triggering apatient-swallowed pill transmitter, the method comprising: under controlof a hardware system comprising a hardware processor, memory, and adisplay: receiving signals from a plurality of antennas disposed about abody of a patient, the signals responsive to a transmitted signal from apill transmitter swallowed by the patient; identifying phase differencesof the received signals based at least partly on mutual inductancebetween the pill transmitter and at least some of the plurality ofantennas; comparing the phase differences with a stored training set,wherein the stored training set comprises measurements of phasemeasurements of a pill transmitting outside of the patient at variousselected locations in a volume surrounded by the plurality of antennas,wherein the plurality of antennas are positioned on a frame toapproximately correspond to locations of the plurality of antennas onthe body of the patient; and determining an initial estimate of alocation of the pill transmitter within the body of the patient based atleast in part on of the comparison of the phase differences with thestored training set and the locations of all the plurality of antennas;and refining the initial estimate by applying a nonlinear process to theinitial estimate to produce a refined estimate of the location of thepill transmitter.
 22. The method of claim 21, further comprisingdetermining locations of all of the plurality of antennas disposed aboutthe body of the patient, wherein the locations of all of the pluralityof antennas may change as the patient moves.
 23. The method of claim 21,further comprising: receiving, from a user interface of the display, auser input indicating a first target location in the patient's body todeliver a medication; and comparing said refined estimate of thelocation of the pill transmitter with the first target location.
 24. Themethod of claim 21, further comprising wirelessly sending a triggersignal to the pill transmitter based on said comparing, the triggersignal configured to cause the pill to deliver the medication responsiveto receiving the trigger signal.
 25. The method of claim 21, wherein theinitial estimate takes into account an orientation of the pilltransmitter with respect to at least some of the plurality of antennas.26. The method of claim 21, further comprising filtering the nonlinearestimate of the location of the pill transmitter to produce an overallestimate of the location of the pill transmitter based at least in parton a previously estimated location of the pill transmitter within thebody of the patient.
 27. The method of claim 21, further comprisingoutputting an indication of the refined estimate of the location of thepill transmitter for presentation to a clinician.
 28. The method ofclaim 21, wherein the pill comprises a reservoir configured to store aquantity of a drug.
 29. The method of claim 21, further comprisingactivating a feature of the pill separate from medication delivery basedin part on the trigger signal.